Targeting proteostasis for cancer therapy: current advances, challenges, and future perspectives

Zhang, Chenliang; Li, Jielang; Tang, Qiulin; Li, Liping; Cao, Dan

doi:10.1186/s12943-025-02472-x

Review
Open access
Published: 21 October 2025

Targeting proteostasis for cancer therapy: current advances, challenges, and future perspectives

Molecular Cancer volume 24, Article number: 265 (2025) Cite this article

935 Accesses
Metrics details

Abstract

The proteostasis network plays a pivotal role in enabling tumor cells to maintain protein homeostasis, mitigate proteotoxic stress, and promote tumor progression and resistance to therapeutic interventions. Targeting proteostasis has garnered considerable attention as a promising anti-cancer strategy, with potential to enhance the efficacy of various therapeutic modalities. In this review, we provide a comprehensive synthesis of the proteostasis regulatory network within tumor cells, elucidating the molecular mechanisms by which proteotoxicity induces cellular damage and death. Furthermore, we present the latest advancements in proteostasis-targeted strategies, offering an in-depth exploration of approaches to sensitize tumor cells to proteotoxic stress, overcome drug resistance, and improve the effectiveness of cancer immunotherapy and radiotherapy. By highlighting the key challenges and emerging research directions, this review aims to provide valuable insights into the development of novel proteostasis-targeted therapies.

Introduction

Protein homeostasis, or proteostasis, refers to the precise balance of protein synthesis, folding, and degradation that is essential for maintaining the integrity and functionality of the cellular proteome [1]. The proteostasis network regulates protein levels and monitors their quality, preventing the accumulation of misfolded or defective proteins that could lead to proteotoxicity [1, 2]. In response to proteotoxic stress, cells either reduce protein synthesis or enhance protein degradation to mitigate or eliminate proteotoxicity. Failure of this stress response results in an imbalance of protein homeostasis, exacerbating cellular damage and triggering proteotoxic cell death, which contributes to various diseases, including neurodegenerative and metabolic disorders [1,2,3,4].

In tumorigenesis, the high rate of protein synthesis—necessary for the rapid proliferation of tumor cells—coupled with elevated genetic mutations, leads to the production of large quantities of dysfunctional or misfolded proteins, contributing to proteotoxic stress. Tumor cells adopt various adaptive mechanisms to alleviate proteotoxic stress, thereby facilitating tumor progression [5, 6]. Disruption of proteostasis in these cells induces proteotoxic cell death, making proteostasis a promising target for cancer therapy. In recent decades, researchers have focused on developing drugs that target proteostasis pathways, such as the ubiquitin-proteasome system (UPS), unfolded protein response (UPR), and heat shock response (HSR), to induce proteotoxic death in tumor cells [7, 8]. These compounds have shown anti-tumor activity in preclinical studies and clinical trials. However, compared to two decades ago, research on proteostasis-targeted cancer therapies has reached a bottleneck, necessitating a review of current findings and the challenges ahead. Furthermore, with the emergence of new cancer treatment strategies and concepts, understanding the relationship between proteostasis and these approaches is crucial. This understanding may not only enhance the therapeutic efficacy of these strategies but also reveal new avenues for targeting proteostasis.

In this review, we systematically summarize the regulatory network of proteostasis in tumor cells, the molecular mechanisms by which proteotoxicity induces cellular damage and death, and the latest developments in proteostasis-targeted cancer therapies. We also explore methods to sensitize tumor cells to proteotoxicity, their molecular characteristics, and discuss the feasibility and mechanisms of targeting proteostasis to overcome tumor drug resistance, enhance cancer immunotherapy, and improve radiotherapy. Finally, we address the challenges in targeting proteostasis for cancer treatment and offer recommendations for future research.

Proteostasis network

The proteostasis network maintains cellular proteome balance by ensuring the correct folding, localization, and assembly of proteins, which are essential for their biological functions. It monitors protein status, prevents misfolded proteins, and promotes their clearance to alleviate proteotoxic stress. This network encompasses protein synthesis, folding, and degradation processes, all of which are interconnected to preserve balance (Fig. 1).

Protein synthesis serves as the initial checkpoint in quality control, involving four steps: initiation, elongation, termination, and ribosome recycling. Initiation, the rate-limiting step, is facilitated by complexes Such as the 43S pre-initiation complex, eIF4F complex, and the 60 S ribosomal complex [9]. Following synthesis, most proteins must fold into Functional 3D structures. Misfolded proteins, characterized by exposed hydrophobic residues and unpaired β-strands, aggregate, triggering cellular stress and damage. While spontaneous folding is driven by the amino acid sequence, it is insufficient for the formation of Fully Functional 3D structures, particularly for multi-domain or complex proteins [3, 10]. Molecular chaperones, including heat shock proteins (HSPs) such as small HSPs, HSP40, HSP60, HSP70, and HSP90, assist in protein folding by binding to misfolded proteins and ensuring proper assembly without becoming part of the final structure [11]. In collaboration with co-chaperones, they prevent or reverse misfolding and aggregation [11].

Protein degradation is another key regulatory step in proteostasis, controlling the quantity of functional proteins, regulating cellular signaling, and preventing the accumulation of harmful proteins, thereby reducing proteotoxicity. Degradation occurs through two main pathways: proteasome-mediated degradation and autophagy-lysosomal pathway (ALP)-mediated protein clearance. The proteasome, a multimeric complex, consists of a 20 S core particle (CP) and a 19 S regulatory particle (RP) [12]. The 20 S core, with trypsin-, caspase-, and chymotrypsin-like activities, is the primary site for substrate degradation [12]. The 19 S RP recognizes and binds ubiquitinated proteins, removes the ubiquitin, and initiates their degradation in the 20 S core [12]. Together, the 20 S core and 19 S RP form the 26 S proteasome, responsible for degrading ubiquitinated proteins [12, 13]. In addition to ubiquitin-dependent degradation, the proteasome can also degrade proteins in an ubiquitin-independent Manner, particularly through the 20S core. Proteins with intrinsically disordered regions (IDRs) can enter the 20 S proteasome in an ATP- and ubiquitin-independent manner for cleavage [14]. Oxidative stress can expose the disordered regions of proteins, allowing them to be degraded by the 20 S proteasome [15]. Some specific proteins, such as PA28αβ, PA28γ, and PA200, that act as proteasome regulatory particles can drive Substrate degradation through ubiquitin-independent mechanisms in the 20S proteasome [16,17,18].

ALP is another crucial protein degradation route. During ALP, misfolded proteins, typically aggregating into clusters, and damaged organelles are sequestered into autophagosomes—double-membraned vesicles [19]. These autophagosomes fuse with lysosomes containing hydrolases, leading to the degradation of their contents [19]. The oligopeptides or amino acids generated in ALP-mediated protein degradation can be transported back into the cytoplasm for de novo biosynthesis. Autophagy-dependent protein degradation relies on autophagy cargo receptors (ACRs) to bind substrates [20]. In mammalian cells, key ACRs, Such as Sequestosome 1 (SQSTM1), neighbor of BRCA1 gene 1 (NBR1), Toll-interacting protein (TOLLIP), and Optineurin (OPTN), contain ubiquitin-binding domains (UBDs) that enable them to recognize and bind ubiquitinated misfolded proteins [20]. Additionally, ACRs possess LC3 (Microtubule-associated protein 1 Light chain 3)-interacting regions (LIRs) that interact with LC3 and other ATG8 (Autophagy-related 8) family proteins, facilitating the delivery of misfolded or aggregated proteins to autophagosomes, which then fuse with lysosomes for degradation [20]. In addition to the autophagosome-dependent process, proteins can also be directed to lysosomes via chaperone-mediated autophagy (CMA), a mechanism that requires molecular chaperones such as HSC70, DNAJB1, and HSP90 [21]. HSC70 recognizes the KFERQ-like motif in Substrate proteins, triggering their unfolding and Subsequent entry into the lysosome through the lysosomal-associated membrane protein 2 (LAMP2) membrane protein [21]. Furthermore, studies suggest that proteins can also be exported via vesicle transport and exosomes, expanding the proteostasis network [22, 23]. However, the regulatory mechanisms and physiological or pathological significance of these processes remain unclear.

Proteotoxic stress response in tumor cells

During tumorigenesis, tumor-driving signaling pathways, such as RAS-MAPK and PI3K-AKT, along with their downstream mTORC1 signaling pathways, enhance protein synthesis [24,25,26]. In addition, the progression of tumors and the development of drug resistance are accompanied by an increased incidence of genetic mutations, including point mutations, duplications, deletions, inversions, and aneuploidy [27]– [28]. These genetic alterations lead to the production of non-functional or inactive proteins, which are often misfolded and toxic. Recent studies have also shown that cancer cells experience transcription elongation defects, associated with malignancy and poor patient outcomes, resulting in high expression of truncated isoforms and accumulation of misfolded proteins [29]. Furthermore, unique environmental characteristics of tumor cells, such as hypoxia, nutrient deprivation, and oxidative stress, contribute to protein damage and the generation of toxic proteins [30, 31]. The accumulation of misfolded and toxic proteins within the cell disrupts proteostasis and induces a proteotoxic crisis. In response, cancer cells employ various adaptive mechanisms—the proteotoxic stress response—to regulate the production and clearance of misfolded proteins, maintaining proteostasis. Enhancing the proteotoxic stress response is thus a hallmark of tumorigenesis. Within cells, multiple regulatory mechanisms exist to respond to proteotoxic stress and maintain proteostasis, including the HSR, UPS, UPR, and ALP. In the following section, we comprehensively summarize these cellular mechanisms, which remodel proteostasis balance during misfolded protein overload, and discuss their roles in tumorigenesis (Fig. 1).

Heat shock response (HSR)

HSR is a highly conserved stress response activated by various cellular stresses, such as heat shock, oxidative stress, glucose depletion, and the overload of misfolded proteins [32]. This response leads to an increase in molecular chaperones, enhancing protein folding efficiency or stabilizing protein conformations, thereby reducing proteotoxicity. HSR is regulated by heat shock transcription factors (HSFs), which are winged helix-loop-helix DNA-binding proteins [33]. Under normal conditions, HSFs exist in a monomeric state bound to chaperones, such as HSP70, chaperonin TRiC (CCT), and HSP90. When misfolded proteins or unstable polypeptides accumulate, chaperones are titrated away from HSFs, leading to the trimerization of HSFs, which can then translocate to the nucleus. There, they recognize and bind to conserved motifs in the promoters of chaperone and co-chaperone genes, upregulating their transcription [34].

Of the six human HSFs (HSF1, HSF2, HSF4, HSF5, HSFX, and HSFY), HSF1 has been the most extensively studied. Elevated nuclear expression of HSF1 has been observed in various tumors, including breast [35], liver [36], lung [37], prostate [38], and pancreatic cancers [39]. Furthermore, high levels of HSF1 correlate with poor prognosis in several cancer patient cohorts [35,36,37,38,39]. In addition to their role in stress response, oncogenic signaling pathways can directly modulate HSF1 activity. For instance, mTOR (mammalian target of rapamycin) from the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B) pathway and MEK (MaP kinase kinase 1) from the MAPK (mitogen-activated protein kinase) pathway can enhance HSF1’s transcriptional activity through phosphorylation at S326 [40,41,42]. These findings indicate that HSF1 serves as a significant oncogenic factor, and its inhibition may represent a potential therapeutic strategy for cancer treatment. In the context of HSR in cancer cells, chaperones such as HSP70s and HSP90s play critical roles as both participants and regulators. Together, HSP70s and HSP90s account for approximately 5.5% of the total protein mass in the cell [43]. These chaperones help reduce the accumulation of misfolded proteins and alleviate proteotoxicity while being essential for the stability and function of important oncogenic proteins.

Ubiquitin-proteasome system (UPS)

UPS-mediated degradation of ubiquitinated proteins is a critical pathway for the cellular clearance of misfolded proteins. A key step in this process is substrate ubiquitination, which occurs through a coordinated enzymatic cascade involving E1 enzymes, E2 enzymes, and E3 ligases [44]. Notably, not all ubiquitination events catalyzed by E3 ligases trigger protein degradation; some modifications act as regulatory signals for essential biological processes, such as epigenetics, cell cycle regulation, DNA repair, and T-cell receptor signaling [45]. In humans, there are two E1 enzymes, nearly 40 E2 enzymes, and approximately 1000 E3 ligases [46]. E3 ligases exhibit substrate selectivity by interacting with substrate molecules to conjugate ubiquitin to lysine or other amino acid residues, facilitating the assembly of diverse polyubiquitin chain structures. Conversely, deubiquitinases (DUBs) can remove ubiquitin from ubiquitinated proteins or cleave ubiquitin chains, thereby stabilizing target proteins by preventing their proteasomal or lysosomal degradation, or modulating ubiquitination signaling to maintain cellular homeostasis [47]. Thus, the regulation of cellular proteostasis by the UPS is a delicate balance between protein ubiquitination and deubiquitination. In addition to maintaining overall proteostasis, the UPS also regulates the stability of key proteins associated with tumors, including oncogenes and tumor suppressor genes, thus influencing nearly all biological behaviors of cancer cells [44].

As the proteasome is the degradation site for ubiquitinated substrates, its normal function is crucial for the efficiency of UPS in cancer cells. Unlike other proteotoxic stress responses such as HSR and UPR, which are considered strict stress responses, the UPS is a physiological process essential for both normal and tumor cells. However, in tumor cells, the enhanced UPS, especially the increased activity of the proteasome, is often necessary to adapt to the proteotoxic environment. Studies have shown that proteasome activity is elevated in various tumors, such as multiple myeloma (MM) [48], colorectal cancer (CRC) [49, 50], and breast cancer [51], and is closely associated with tumor progression and poor prognosis. Interestingly, cancer stem-like cells (CSCs)—a small reservoir of self-renewing cells that play pivotal roles in tumorigenicity, metastasis, recurrence, and treatment resistance—exhibit reduced proteasome activity. For example, Koji et al. demonstrated that in colorectal cancer, proteasome activity negatively correlates with the stemness of tumor cells, with those exhibiting low proteasome activity showing greater resistance to radiation, chemotherapy, and increased sphere formation [52]. In vitro studies of non-small cell lung cancer (NSCLC) cell Lines have also observed decreased 26S proteasome activity in tumor spheres compared to monolayer cells [53]. These findings suggest that the impact of proteasome activity on tumor cell fate varies during different stages of tumor progression, likely due to changes in key regulatory factors involved in proteasomal degradation.

Unfolded protein response (UPR)

The endoplasmic reticulum (ER) is a crucial organelle involved in the synthesis, storage, folding, maturation, and transportation of proteins, particularly secretory proteins. As such, the ER plays a central role in maintaining protein homeostasis within the cell. When proteins in the ER fail to fold correctly, they are retro-translocated to the proteasome for degradation, a process known as ER-associated degradation (ERAD) [54]. ERAD is a complex mechanism involving multiple proteins from both the ER and cytoplasm, including ubiquitin E3 ligases located on the cytoplasmic face of the ER membrane, Such as HMG-CoA reductase degradation 1 (HRD1), glycoprotein 78 (Gp78), and cell growth regulator with RING finger domain protein 1 (CGRRF1), as well as the cytosolic ATPase valosin-containing protein (VCP) (also known as p97) [54, 55]. p97/VCP plays a pivotal role in ERAD by providing the energy necessary for retro-translocation and mechanically assisting in protein unfolding, facilitating substrate delivery to the proteasome for degradation [56]. The accumulation of misfolded or unassembled proteins in the ER induces a toxic state known as ER stress. In response, the ER activates an adaptive signal transduction pathway called the UPR, which reduces the synthesis of new proteins while enhancing the folding and degradation of misfolded proteins in the ER [57]. This response helps alleviate the cellular stress caused by proteotoxicity, thereby maintaining proteostasis.

The activation of the UPR in cells is primarily controlled by three ER stress sensors: protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). These sensors are transmembrane proteins embedded in the ER membrane. Under basal conditions, their luminal domains are bound to BiP (also known as GRP78, a key ER chaperone), which inhibits their activity [57]. When unfolded proteins accumulate in the ER, BiP dissociates from the UPR sensors and binds to the exposed hydrophobic regions of these proteins. This binding activates the sensors, initiating downstream signaling cascades [57]. These cascades regulate the transcription of genes involved in ER chaperones, ERAD, mRNA detachment from the ER membrane, lipid synthesis, protein secretion, apoptosis, and autophagy [57].

PERK, a transmembrane protein with a cytosolic kinase domain, undergoes dimerization and trans-autophosphorylation, releasing its kinase activity. This allows PERK to phosphorylate eukaryotic translation initiation factor 2α (eIF2α). Phosphorylated eIF2α binds tightly to eIF2B, inhibiting translation initiation and reducing global protein synthesis [57, 58]. However, eIF2α phosphorylation enhances the translation of activating transcription factor 4 (ATF4), as ATF4 mRNA can bypass the eIF2α-mediated translational repression through non-canonical initiation [57, 59]. Upon translocation to the nucleus, ATF4 promotes the expression of the pro-apoptotic CCAAT/enhancer-binding protein homologous protein (CHOP) [57,58,59]. ATF4 and CHOP together activate the transcription of UPR genes. Once proteostasis is restored and ER stress alleviated, ATF4 and CHOP induce the transcription of DNA damage-inducible protein 34 (GADD34), a regulatory Subunit of G-actin and protein phosphatase 1 (PP1) that catalyzes the dephosphorylation of p-eIF2α [57, 60].

Similarly, the dissociation of BiP triggers IRE1 oligomerization in the ER membrane and trans-autophosphorylation by its cytosolic kinase domain, activating its endonuclease domain [57]. IRE1’s endonuclease catalyzes the unconventional splicing of XBP1 mRNA, excising a 26-nucleotide intron with the help of RNA ligase RTCB (RNA 2’,3’-cyclic phosphate and 5’-OH ligase). The resulting mRNA is translated into the stable, active transcription factor XBP1s, which promotes the transcription of UPR genes [57, 61]. Additionally, IRE1 can degrade RNAs through regulated IRE1-dependent decay (RIDD), including ER-localized mRNAs, ribosomal RNA, and microRNAs, thereby alleviating the translation burden of ER client proteins [57, 62].

ATF6, a transmembrane transcription factor, is exported from the ER During stress and traffics to the Golgi apparatus. There, it is cleaved by site 1 protease (S1P) and site 2 protease (S2P), generating a cytosolic fragment (ATF6f) with transcription factor activity [63,64,65]. ATF6f translocates to the nucleus, where it activates the transcription of UPR genes involved in protein folding, ERAD, and lipid biogenesis [65, 66]. Furthermore, ATF6f can form heterodimers with XBP1s to regulate distinct gene expression patterns [67].

The UPR is another critical mechanism by which tumor cells manage proteotoxic stress. In various tumors, including breast [68], pancreatic [69], gastric [70, 71], hepatocellular carcinoma (HCC) [72], prostate cancer [73], and glioblastoma (GBM) [74], UPR activation facilitates tumor growth and resistance to therapeutic agents. Interestingly, the activation status of downstream UPR sensors varies at different stages of tumor development. For example, in HCC during tumor initiation, IRE1 signaling peaks, while during tumor progression, the PERK pathway is predominantly activated, and ATF6 signaling is modestly activated only after tumor initiation [75]. In vitro and in vivo studies of HCC have demonstrated that under ER stress or hypoxia, only the PERK inhibitor—not the IRE1 inhibitor—reduces cell viability and proliferation by increasing proteotoxic stress [75]. These findings suggest that different arms of the UPR play distinct roles at various stages of tumor development, warranting further research into the dynamic changes and mechanisms involved.

Integrated stress response (ISR)

Integrated stress response (ISR) is a biological response that cells use to cope with various stressors, including nutrient deprivation, oxidative stress, and viral infections. It modulates cellular metabolism, protein synthesis, and survival through a network of signaling pathways, helping cells adapt to adverse conditions. Within the proteostasis regulation network, ISR plays a vital role in mitigating cellular proteotoxic stress and facilitating entry into a protective state. Consequently, ISR represents a key mechanism by which tumor cells resist proteotoxic stress. ISR shares part of its regulatory network with the UPR, notably the eIF2α-ATF4 signaling pathway, which is the core of ISR [76]. Upon activation of stress responses, ISR regulators—EIF2AKs, including PERK, GCN2, HRI, and PKR—are activated, leading to phosphorylation of eIF2α. This reduces global translation while enhancing ATF4 expression and promoting cellular autophagy, thus contributing to protein quality control [76]. In tumor cells exposed to proteotoxic stress, ISR aids their resistance to proteotoxicity. Sara Sannino and colleagues observed that activation of GCN2 leads to tumor cell resistance against HSP70 inhibitors, while supplementation with amino acids or activation of mTORC1 can diminish this GCN2-mediated resistance [31]. Additionally, ISR has been found to promote the translation of centrosomal proteins, enhancing centrosomal microtubule dynamics [77]. This facilitates the migration of aggregated misfolded proteins to the microtubule-organizing center (MTOC) to form aggresomes, perinuclear structures that sequester misfolded proteins and mitigate their proteotoxicity [77].

Autophagy-lysosome pathway (ALP)

Autophagy-dependent lysosomal degradation is a primary manifestation of ALP. Although ALP is not classified as a strict proteotoxic stress response, it serves as a fundamental biological process essential for maintaining normal physiological functions in cells. Nevertheless, ALP plays a crucial role in protein degradation, specifically in tumor cells. In the context of cellular proteostasis, autophagy primarily targets aggregated misfolded proteins, a process known as aggrephagy, which is mediated by specialized ACRs [78]. Additionally, a newly identified process, ER-phagy, involves the lysosomal degradation of the ER and its components, contributing to the degradation of accumulated misfolded proteins within the ER lumen [79, 80]. This provides a new theoretical framework for understanding how autophagy maintains proteostasis. Future studies should focus on the role of ER-phagy in tumorigenesis and tumor progression, aiming to uncover new therapeutic targets and strategies. Interestingly, recent studies have revealed crosstalk between autophagy and extracellular vesicle secretion. Research by Tina A et al. has demonstrated that when autophagosome-lysosome fusion is inhibited or endolysosomal function is compromised, autophagosomes containing autophagic cargo receptors can form amphisomes with late endosomes [81]. These amphisomes are then released as extracellular vesicle particles through Rab27a-dependent exocytosis at the plasma membrane [81]. This mechanism prevents the accumulation of proteins that require degradation, providing a molecular basis for understanding how autophagy regulates the tumor microenvironment derived from tumor cells.

Crosstalk between different mechanisms of proteotoxic stress response

The maintenance of proteostasis within cells is not governed by a single signaling pathway; rather, these regulatory pathways interact and compensate for one another. For example, downstream effectors of UPR, such as ATF4 and CHOP, can enhance the expression of key autophagy regulators, including LC3B and ATG5, thereby promoting autophagic flux [82,83,84]. Additionally, C-Myc and N-Myc can upregulate protein synthesis and activate the UPR, facilitating cytoprotective autophagy and promoting colony formation and tumor development [85, 86]. Moreover, proteasomal activity is also linked to the UPR. When proteasomal activity is diminished or inhibited, the degradation of misfolded proteins via the proteasome is impaired, resulting in ER stress that activates UPR signaling pathways [87,88,89]. While the UPR promotes the clearance of misfolded proteins, it also concurrently inhibits eIF2α-dependent protein translation. In addition, there is crosstalk between UPS and ALP. Ubiquitination initiates UPS for protein degradation and serves as a signal for autophagic degradation. Most ACRs recognize and bind to substrates via ubiquitin chains, enabling the degradation of ubiquitinated proteins through both the UPS and autophagy pathways [90]. Tumor regulatory factors, such as HIF1α, programmed cell death Ligand 1 (PD-L1), and p53, can be degraded through both the UPS and ALP following ubiquitination. Typically, the autophagy pathway targets aggregated ubiquitinated proteins, while the UPS primarily handles free, cytosolic ubiquitinated proteins. Thus, the ability of tumor cells to thrive amidst proteotoxic stress arises from the integrated actions of HSR, UPS, UPR, and ALP. Considering the impact of proteostasis pathways on tumor outcomes at the individual molecular level may be limited, as they regulate the degradation of both tumor-promoting and tumor-suppressing factors. Therefore, future studies should focus on the effects of global proteostasis imbalance on tumor cell growth and patient outcomes, providing a more comprehensive framework for evaluating targeted proteostasis strategies in anticancer therapies.

Proteotoxicity-induced tumor cell death

Severe proteotoxic stress can lead to cellular injury and ultimately induce cell death, providing a critical theoretical foundation for targeting proteostasis in cancer therapy. As previously discussed, the regulation of proteostasis within cells is multifaceted, and similarly, cell death resulting from proteotoxicity occurs through various mechanisms, including apoptosis, ferroptosis, necrosis, paraptosis, and cuproptosis (Fig. 2).

Apoptosis

Severe proteotoxic stress, induced by ER stress or impaired UPS function, has been shown to trigger apoptosis in various cell types. Mechanistically, proteotoxic stress can alter the expression levels of key apoptosis regulatory factors. ATF4 and CHOP play central roles as executors of this process by upregulating pro-apoptotic factors Such as death receptor 5 (DR5), growth arrest and DNA damage-inducible protein 34 (GADD34), phorbol-12-myristate-13-acetate-induced protein 1 (NOXA), Bcl-2 interacting mediator of cell death (Bim), and p53 upregulated modulator of apoptosis (PUMA), while simultaneously downregulating anti-apoptotic factors, including B-cell lymphoma 2 (BCL-2), myeloid cell leukemia 1 (Mcl-1), B-cell lymphoma-extra large (BCL-XL), and X-linked inhibitor of apoptosis (XIAP) [8, 91]. These factors initiate apoptosis by modulating various signaling pathways, including the mitochondrial-associated and death receptor-mediated apoptotic pathways. In addition to modulating the transcriptional levels of apoptotic factors, proteotoxic stress can initiate apoptosis through alternative signaling pathways. In the context of the extrinsic pathway of caspase activation-mediated apoptosis, severe ER stress, PERK activation, and UPS inhibition can upregulate the expression of TNFRSF10B/DR5, the TRAIL receptor, which induces apoptosis via the extrinsic pathway of caspase activation [92,93,94]. Studies have also shown that misfolded proteins can cause DR5 to oligomerize at the Surface of the ER-Golgi intermediate compartment, activating caspase 8 in a TRAIL-independent manner [95, 96]. Additionally, ER stress can enhance the stability of pro-apoptotic factors, such as Bim and BOK, leading to their accumulation and the initiation of apoptosis [97, 98]. Another regulatory factor closely related to proteotoxic stress-induced apoptosis is nuclear factor Kappa-B (NF-κB), which plays a dual role in the process. NF-κB can promote anti-apoptotic factor expression (e.g., BCL2, BCL-XL) upon activation, partially inhibiting apoptosis, or trigger apoptosis through the TRAIL-mediated extrinsic pathway and p53 modulation [8, 91, 99]. Studies show that proteasome inhibition affects NF-κB differently across tumor types: in Waldenström macroglobulinemia [100], chronic lymphocytic leukemia [101], and breast cancer [102], it suppresses NF-κB nuclear translocation, while in MM [103], ovarian cancer [104], and intrahepatic cholangiocarcinoma [105], it promotes NF-κB activity. Additionally, ER stress inducers activate NF-κB in cervical cancer cells [106], counteracting apoptosis, while in breast cancer cells [107], estrogen enhances NF-κB activity, promoting apoptosis. These findings underscore the selective nature of NF-κB signaling in response to proteotoxic stress and highlight the need to understand the distinct mechanisms in tumor cells for targeted cancer therapies.

Ferroptosis

Ferroptosis is a distinct form of regulated cell death (RCD) characterized by iron dependency and the accumulation of lipid peroxides. Emerging evidence indicates that proteotoxic stress plays a critical regulatory role in the ferroptotic signaling pathways of tumor cells. One major regulator is the HSR, which exerts a suppressive effect on ferroptosis. High expression of HSF1 has been shown to protect tumor cells by reducing reactive oxygen species (ROS) levels and lipid peroxidation, thereby conferring resistance to ferroptosis inducers such as RSL3 and Erastin [108, 109]. UPS and UPR/ER stress pathways are also intricately involved in ferroptotic regulation. While reduced proteasome activity and aggravated ER stress have been observed during ferroptosis, the roles of these systems are complex. Both positive and negative regulatory proteins of ferroptosis are reported to be degraded via the UPS, while their gene transcription can be enhanced by the ATF4-CHOP axis activated by ER stress [110]. Interestingly, our previous work in HCC revealed that ferroptotic signaling may facilitate the exosomal clearance of misfolded proteins during proteasome inhibition, thereby alleviating ER stress-associated cell death [111]. Although the precise mechanisms remain to be elucidated, these findings highlight the potential of ferroptosis pathways in mitigating proteotoxic stress-induced damage. A central mediator connecting proteotoxic stress with various forms of PCD is ROS. Elevated ROS—resulting from proteasome inhibition, HSR dysfunction, or unresolved ER stress—not only promotes apoptosis via DNA damage and activation of the p53–JNK axis, but also accelerates lipid peroxidation, thereby driving ferroptosis [112]. These observations underscore the multifactorial nature of proteotoxic stress in tumor cell fate decisions. In conclusion, inducing proteotoxic stress-associated ferroptosis represents a promising strategy for cancer therapy. However, its effectiveness depends on multiple variables, including tumor type, the mode of proteotoxic stress induction, and the cellular redox environment. Rational modulation of these factors may enable precise enhancement of ferroptosis in tumor cells, thereby improving therapeutic outcomes.

Necrosis

Although cells treated with proteasome inhibitors or ER stress inducers often exhibit necrotic phenotypes, the precise conditions and molecular mechanisms through which proteotoxic stress induces necrosis remain poorly understood. Current research suggests that necrosis, in the context of proteotoxic stress, may function as a compensatory form of injury resulting from the inhibition of apoptosis. For example, E. Ullman et al. found that in bax^−/−bak^−/− cells, where apoptosis is blocked, autophagy activated by ER stress exacerbates necrosis, a phenomenon not observed in wild-type cells [113]. Indeed, when caspase-dependent apoptosis is suppressed during cellular stress, necroptosis—an alternative form of programmed cell death mediated by a complex of receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL)—can be activated, exacerbating cell injury [114, 115]. Caspase-8 activation inhibits necrosome formation, suggesting that caspase-8 activation induced by proteotoxic stress may suppress necroptosis [116]. Additionally, research highlights the presence of anti-necroptosis signaling pathways during ER stress. For instance, in hepatocytes, ER stress-induced necroptosis independent of TNFR1 signaling can be inhibited by phosphorylated eIF2α [117]. Ma et al. demonstrated that in lung cancer cells, drug-induced activation of CHOP mediates RIP1-dependent necroptosis rather than apoptosis [118]. This cytotoxic effect could be reversed by the ROS scavenger N-acetyl-L-cysteine. Furthermore, studies show that hypoxia exacerbates necrosis in proteasome inhibitor-treated colon cancer cells [119]. Diane R. Fels et al. found that hypoxic tumor cells are more sensitive to proteasome inhibitors, leading to more severe ER stress [120]. These findings suggest that the redox environment influences the mode of cell death triggered by proteotoxic stress, with ROS potentially promoting a shift from apoptosis to necrosis. Given that hypoxia is a hallmark of solid tumors that drives tumor growth, angiogenesis, and metastasis, targeting proteostasis may offer therapeutic advantages for treating hypoxic tumors.

Paraptosis

Paraptosis is a form of programmed cell death that is closely associated with proteotoxic stress. Unlike classical apoptosis, paraptosis is morphologically distinct: it does not involve DNA fragmentation, caspase activation, or the formation of apoptotic bodies [121]. Instead, it is characterized by the dilation of the ER and/or mitochondria, accompanied by the accumulation of misfolded proteins, excessive production of ROS, and pronounced ER stress [121]. Experimental evidence demonstrates that inhibiting protein synthesis or preventing the accumulation of misfolded proteins can effectively suppress paraptosis, indicating that proteotoxicity serves as a primary inducer of this cell death modality. Although the precise molecular mechanisms underlying paraptosis remain incompletely understood, numerous studies suggest that disruptions to cellular proteostasis—such as proteasome inhibition and aggravated ER stress—can initiate this process [122,123,124]. This has led to the proposition that enhancing the accumulation of misfolded proteins in tumor cells may represent a viable therapeutic strategy to induce paraptosis. However, current evidence indicates that proteasome inhibition, while necessary, is not sufficient on its own to trigger paraptosis. On one hand, additional cellular disturbances—such as perturbations in intracellular Ca²⁺ homeostasis—are required. For instance, in breast cancer cells, paraptosis induced by silencing or pharmacological inhibition of the 19 S proteasome subunit PSMD14 was dependent not only on proteasome dysfunction but also on intracellular Ca²⁺ imbalance [125]. Similarly, Lee et al. reported that Lercanidipine, an antihypertensive drug, can induce mitochondrial Ca²⁺ overload and trigger paraptosis across multiple cancer cell types, thereby enhancing the cytotoxic effects of proteasome inhibitors [126]. On the other hand, intrinsic cellular defense mechanisms against proteotoxic stress can inhibit paraptosis. The ISR, for example, maintains proteostasis through phosphorylation of eIF2α via activation of eIF2α kinases (EIF2AKs) [76]. Studies have shown that the combined use of eIF2α inhibitors and proteasome inhibitors can promote paraptosis in tumor cells [127]. Furthermore, our previous work demonstrated that during proteasome inhibition, CaMKII can phosphorylate BAG3 (BCL2-associated athanogene-3), activating the HRI-eIF2α pathway to mitigate misfolded protein accumulation [128]. Disrupting this CaMKII–BAG3–HRI–eIF2α axis effectively triggers paraptosis under proteasome-inhibited conditions [128]. In summary, current findings support the notion that paraptosis is a consequence of severe proteotoxic stress. These insights underscore the therapeutic potential of combinatorial strategies that exacerbate proteostasis disruption while concurrently inhibiting cellular stress responses, thereby selectively inducing paraptosis in cancer cells.

Cuproptosis

Recently, proteotoxic stress has been implicated in the regulatory mechanisms underlying cuproptosis, a novel form of RCD identified by Tsvetkov et al. Cuproptosis is characterized by the accumulation of excessive copper in the mitochondria [129, 130]. When Cu⁺ concentrations reach critical levels within mitochondria, Cu⁺ binds to lipoylated DLAT (dihydrolipoamide S-acetyltransferase), promoting DLAT oligomerization and subsequently reducing the levels of iron-sulfur (Fe–S) cluster proteins [129, 130]. These events induce mitochondrial proteotoxic stress, ultimately leading to cell death. Moreover, Tsvetkov et al. observed that cells resistant to proteasome inhibitors exhibit enhanced oxidative phosphorylation, which promotes the onset of cuproptosis [129, 131]. This finding suggests a potential strategy for reactivating the proteotoxic crisis in cells resistant to proteasome inhibitors. Although the precise molecular mechanisms by which mitochondrial proteotoxic stress triggers cuproptosis remain unclear, the phenomenon presents a novel avenue for targeting proteostasis in cancer therapy. Notably, the association between copper, a heavy metal implicated in the development of various tumors, and proteostasis offers promising opportunities for manipulating copper levels to disrupt protein homeostasis, providing a potential therapeutic approach for cancer treatment.

Targeting proteostasis for cancer therapy

Over the past few decades, extensive efforts have been made to develop compounds and drugs that disrupt the functions of the proteasome, ER, HSPs, and ALP, aiming to induce proteotoxic cell death. This section will discuss the current progress and challenges in targeting proteostasis for cancer therapy.

Targeting UPS

Targeting the proteasome has become one of the most extensively studied and established approaches for inducing proteotoxic cell death in cancer therapy. Bortezomib, a reversible 20 S proteasome inhibitor, exerts its effects by binding to the β5 Subunit, thereby inhibiting the proteolytic activity of the 20S proteasome [132]. Clinically, Bortezomib has been approved as a monotherapy or in combination with drugs such as dexamethasone, thalidomide, doxorubicin, melphalan, and prednisone for the treatment of MM. It is also approved for use in combination with agents like doxorubicin, rituximab, prednisone, and cyclophosphamide for the treatment of untreated mantle cell lymphoma (MCL) in patients not eligible for hematopoietic stem cell transplantation [132]. However, due to its low selectivity for tumor tissues, Bortezomib treatment is often associated with certain side effects, including thrombocytopenia, cardiovascular complications, and peripheral neuropathy [132, 133]. Carfilzomib, a second-generation proteasome inhibitor, irreversibly and selectively inhibits the 20 S proteasome [132, 134]. It has been approved for clinical use, both as a monotherapy and in combination with other drugs, for treating MM [132]. Compared to Bortezomib, Carfilzomib provides stronger proteasome inhibition with reduced off-target effects. Furthermore, Carfilzomib’s irreversible binding enables it to more effectively inhibit mutated β5 subunits that mediate resistance to Bortezomib in tumor cells [132]. Ixazomib, an orally administered, highly selective second-generation reversible proteasome inhibitor, has been approved for MM treatment in combination with lenalidomide and dexamethasone in patients who have received at least one prior therapy [132, 134]. In addition, Oprozomib and Delanzomib, two other oral 20 S proteasome inhibitors, are currently being evaluated in clinical trials for their safety and efficacy in treating various hematological malignancies and solid tumors [132, 134]. Marizomib, a non-peptidic proteasome inhibitor derived from marine natural products, has demonstrated promising antitumor effects and favorable tolerability in clinical trials. Notably, Marizomib can cross the blood-brain barrier, which has led to its designation as an orphan drug for treating MM and gliomas by the Committee for Orphan Medicinal Products and the FDA [135, 136]. Future preclinical and clinical trials should focus on expanding its use to a broader range of tumor types, particularly in solid tumors, to maximize the potential benefit for patients.

In addition to the aforementioned approved drugs and those currently in clinical trials, researchers have identified or developed several preclinical 20 S proteasome inhibitors, such as Celastrol [137, 138], LU-102 [139], and PI-083 [140]. Moreover, small-molecule inhibitors targeting the 19 S proteasome have also been developed, including b-AP15 [141], WP1130 [142], and Capzimin [143]. Preclinical studies have demonstrated that these 19 S proteasome inhibitors can induce proteotoxic stress, oxidative stress, and apoptosis in various tumor cell types, including those from hematological malignancies and solid tumors, ultimately promoting tumor cell death (Table 1). Additionally, E1 ubiquitin ligases and E2 conjugating enzymes have been explored as drug targets to treat cancer. Notable examples include E1 ligase inhibitors such as TAK-243 [144, 145] and PYR-41 [146] and E2 conjugating enzyme inhibitors like NSC697923 [147]. Whether these compounds could induce proteotoxic cell death is unclear. Recently, metal-based complexes, including transition metal complexes of copper, cadmium, and manganese, have emerged as a novel strategy to target the proteasome, providing a new perspective on metal-based tumor therapies [148].

Table 1 Compounds targeting proteostasis in tumor cells

Full size table

Targeting UPR

Targeting IRE1

The cytoplasmic kinase and RNase domains of IRE1 are critical for activating downstream signaling pathways. IRE1 inhibitors can be classified into those targeting the RNase activity and those targeting the kinase activity. Currently, IRE1 RNase inhibitors, Such as 4µ8c, MKC8866, STF-083010, and MKC9989, have shown effective inhibition of ER stress-associated XBP1 mRNA splicing and RIDD in preclinical studies involving various cancer cells, along with significant anti-tumor efficacy (Table 1) [160,161,162]. Kinase inhibitors targeting IRE1’s kinase activity are divided into Type I and Type II kinase inh128ibitors. Type I inhibitors competitively bind to the ATP binding pocket in the kinase domain, inducing an active conformation, whereas Type II inhibitors bind to the ATP pocket in the inactive conformation. Type II inhibitors, therefore, act as true inhibitors of IRE1’s enzymatic activity, suppressing its kinase activity and, consequently, preventing the activation of its RNase activity. As shown in Table 1, Type II kinase inhibitors of IRE1, including KIRA8 (AMG-18) and GSK2850163 inhibit both kinase and RNase activities of IRE1, exhibiting significant anti-tumor functions in preclinical studies [160,161,162].

Targeting PERK

PERK primarily transmits UPR signaling through its protein kinase activity. Various compounds targeting this kinase activity have been developed to disrupt PERK functions and exhibit anti-tumor efficacy (Table 1). Among these, GSK2606414 is a widely used PERK inhibitor in preclinical studies, effectively inhibiting the growth of drug-resistant tumor cells in breast cancer [163], CRC [164], and pancreatic cancer [165]. Several analogues of GSK2606414 have been designed to target the ATP-binding site of PERK, including GSK2656157, PERK-IN-2, and PERK-IN-3 [166]. However, these inhibitors are not substrate-specific for PERK. For instance, GSK2606414 and GSK2656157 also inhibit phosphatidylinositol phosphate kinases (PIPK) [167]. AMG-44, a potent and selective PERK inhibitor developed by Smith et al., has been shown to enhance tumor immunotherapy by inhibiting the PERK pathway in tumor-associated myeloid-derived suppressor cells, thereby increasing their immunosuppressive activity and enhancing CD8 + T cell-mediated immunity against cancer [168, 169]. More recently, Calvo et al. developed HC-5404, a highly potent and orally bioavailable PERK inhibitor, currently undergoing Phase I clinical trials for solid tumor therapy [170]. Both in vivo and in vitro studies have demonstrated that HC-5404 targets pre-existing or therapy-induced growth-arrested cells and significantly sensitizes renal cell carcinoma cells to VEGF receptor tyrosine kinase inhibitors (VEGFR-TKIs) [171]. These findings suggest that HC-5404 is a promising candidate for clinical application as a PERK inhibitor.

Targeting ATF6

Ceapin is one of the most widely used selective inhibitors of ATF6 in the study of the UPR. It functions by tethering ATF6 and the peroxisome-localized transmembrane transporter ABCD3, blocking the vesicular transport of ATF6 from the ER to the Golgi apparatus, which inhibits the cleavage of ATF6 [172,173,174]. It is shown that Ceapin can trigger or exacerbate tumor cell death by inhibiting ATF6 functions within the UPR [175, 176]. However, due to the isoxazole substructure of Ceapin, its pharmacokinetic properties may be affected by hepatic metabolism, warranting further investigation in animal models. Moreover, since the nuclear activation of ATF6 relies on cleavage mediated by SP1/SP2 in the Golgi apparatus, targeting the enzymatic activity of SP1/SP2 could indirectly inhibit ATF6 activation. Future research should focus on the development of new, highly selective ATF6 inhibitors, which will provide additional therapeutic options for targeting UPR and ATF6 in cancer treatment.

ER stressors

Severe ER stress can exacerbate proteotoxicity by obstructing the refolding or clearance of misfolded proteins. Consequently, inducers or aggravators of ER stress represent potential strategies for targeting proteostasis in tumor therapy. One significant trigger of ER stress is the abnormal accumulation of misfolded proteins. In this context, inhibitors of the UPS, such as Bortezomib and b-AP15, induce ER stress by inhibiting the degradation of misfolded proteins [177, 178]. Additionally, ER serves as a major reservoir for calcium ions within cells, and disrupting calcium homeostasis in the ER impairs protein folding, thereby triggering ER stress. For example, inhibitors of the sarcoplasmic/ER calcium ATPase, such as Thapsigargin and Celecoxib, disrupt calcium balance in the ER, inducing ER stress and proteotoxicity in tumor cells [179,180,181]. Moreover, inhibiting enzymes involved in protein folding or modification in the ER can also lead to the accumulation of misfolded proteins, thus provoking ER stress. Tunicamycin, an important ER stressor in experimental research, impairs protein folding by inhibiting glycosylation in the ER [182, 183]. Similarly, Secoemestrin C, a natural compound derived from the endophytic fungus Emericella, induces protein misfolding and ER stress by sulfating cysteines, disrupting disulfide bond formation in ER proteins [184]. Furthermore, the arms of the UPR signaling pathway are key components of the ER stress response mechanism. Excessive activation of these UPR arms may induce cellular responses characteristic of ER stress, leading to cellular damage. However, the implications of these effects on proteostasis and their potential as targets for cancer treatment warrant further investigation.

Targeting ERAD

Moreover, blocking ERAD can lead to an imbalance in ER proteostasis. Current strategies to inhibit ERAD primarily focus on suppressing the function of VCP/p97. Eeyarestatin 1 is a commonly used ERAD inhibitor that prevents VCP/p97-associated deubiquitinating enzymes from removing ubiquitin from ERAD substrates, resulting in the accumulation of these substrates in the cytoplasm [188, 189]. However, the molecular mechanism by which Eeyarestatin 1 inhibits ERAD remains unclear, despite evidence that it directly binds to VCP/p97 without affecting its functionality. In addition, several covalent and allosteric inhibitors of VCP/p97 have been developed, such as NMS-859 and NMS-873 [190], which exhibit varying inhibitory effects on ERAD and show some capacity to induce tumor cell death (Table 1). N2,N4-dibenzylquinazoline-2,4-diamine (DBeQ) and its analogs (CB-5083, CB-5339) are selective ATP-competitive inhibitors of VCP/p97 that inhibit ERAD in tumor cells, inducing unresolved proteotoxic stress and leading to apoptotic cell death [191,192,193,194,195]. Among these, CB-5083 and CB-5339 are currently undergoing clinical trials for the treatment of solid tumors and lymphomas due to their low off-target effects, decreased maximum concentration, and reduced clearance rate.

Targeting ISR

Recently, specific ISR inhibitors, such as ISRIB, have been developed. ISRIB inhibits eIF2α’s translational control by binding to it, promoting protein synthesis. Several studies have demonstrated that combining ISRIB with proteotoxic inducers significantly enhances proteotoxic cell death in tumor cells [127, 128]. The ISRIB-based therapeutic ABBV-CLS-7262 has entered clinical development for treating Major Depressive Disorder and Vanishing White Matter Disease [NCT06618118, NCT05757141]. Future research could explore the combination of ABBV-CLS-7262 with proteotoxic inducers for cancer treatment. Recent findings reveal a close link between stress granules (SGs) and the ISR, offering new insights into tumorigenesis and potential cancer therapies [197]. SGs are membrane-less ribonucleoprotein assemblies that form when translation initiation stalls, containing mRNAs, ribosomal subunits, and RNA-binding proteins [198]. ISR activation via eIF2α phosphorylation promotes SG formation by creating stalled translation complexes and accumulating untranslated mRNAs [197]. Given that SGs aid in stress adaptation, treatment resistance, and metabolic reprogramming in tumor cells, targeting ISR-induced SG formation could be a promising strategy for alleviating ISR-induced proteotoxicity in cancer treatment. Moreover, upstream regulatory signals in the ISR can also serve as drug targets to disrupt the ISR-associated proteotoxic stress response. For instance, inhibiting CaMKII can block the BAG3-mediated activation of HRI-eIF2α, thereby enhancing the anti-tumor effects of proteasome inhibitors both in vitro and in vivo [128]. In summary, ISR is a critical mechanism by which tumor cells resist proteotoxic stress. Future research investigating the molecular mechanisms by which ISR regulators respond to different proteotoxic inducers will aid in developing novel strategies to sensitize tumor cells to proteotoxicity.

Targeting HSR

Although HSF serves as an upstream regulator of HSR, its druggability is limited due to its protein characteristics, and no specific drugs or small molecules currently target HSF. Several studies have shown that compounds such as KRIBB11 [199], and KNK437 [200] can inhibit HSF-mediated expression of HSPs by preventing HSF binding to DNA. Future research focused on the development of drugs and strategies targeting HSF1 are essential. RNA-based drugs and proteolysis-targeting chimeras (PROTACs) represent promising therapeutic approaches that may overcome the challenges associated with drug development for HSF proteins.

In contrast to HSF, the development of targeting strategies for HSP70 and HSP90 is relatively more advanced. Structurally, HSP70 consists primarily of an N-terminal nucleotide-binding domain (NBD) with ATPase activity and a substrate-binding domain (SBD). Inhibitors targeting HSP70 have primarily focused on its ATPase activity. VER-155,008, a well-known HSP70 inhibitor, targets the ATPase binding domain of HSP70 to block its function [201]. Preclinical studies have shown that VER-155,008 exhibits antitumor effects in lung cancer [202], prostate cancer [203], and pheochromocytoma [204]. The chaperone function of HSP70 in protein folding requires the assistance of co-chaperones, such as the J-protein family (HSP40s), which activate HSP70’s ATPase activity. MAL3-101 blocks the interaction between HSP70 and the HSP40 co-chaperone, inhibiting HSP70’s ATPase activity [205]. Furthermore, BAG3, a co-chaperone of HSP70, forms a functional complex crucial for misfolded protein quality control, particularly in proteasomal stress-induced clearance of misfolded proteins via autophagy [206]. The compound JG-98 disrupts the HSP70-BAG3 complex, inducing DNA damage and severe ER stress in tumor cells, which inhibiting tumor cell growth [207].

HSP90 comprises an N-terminal domain containing the ATP binding site, a C-terminal domain responsible for co-chaperone binding and protein complex assembly via the MEEVD motif, and a middle domain that mediates interactions with various substrate proteins [208]. The HSP90 family includes two isoforms: HSP90α, an inducible isoform associated with oncogenic activity in tumors, and HSP90β, which is constitutively expressed [208]. HSP90 inhibitors are primarily classified into ATP-competitive inhibitors, which bind to the N-terminal nucleotide-binding pocket, and C-terminal-targeting drugs, which affect HSP90’s interaction with substrates and its oligomerization. First-generation N-terminal inhibitors, such as Geldanamycin, Tanespimycin (17-AAG), and their derivatives (Table 1), have shown efficacy, but their use is limited by the upregulation of HSP70 and HSP90, which contributes to drug resistance in tumor cells [209,210,211]. These agents also lack specificity for HSP90α, inhibiting HSP90β, the mitochondrial isoform TRAP1, and the ER isoform grp94, leading to unacceptable toxicity in vivo [212]. Second-generation N-terminal inhibitors have been developed to address these limitations, offering improved specificity and reduced toxicity. Among them, luminespib has been reported to suppress tumor growth by enhancing proteotoxicity [213]. Targeting the C-terminal domain of HSP90 allows for allosteric control over the N-terminal binding site, preventing the upregulation of HSP70 and HSP90. Compounds such as novobiocin [214, 215], mycotoxin [216], have been shown to bind the C-terminal domain of HSP90 and inhibit tumor cell growth. However, their effects on tumor cell proteostasis are still unknown.

Targeting ALP

Current research indicates that inhibiting autophagy flux in tumor cells may exhibit some antitumor efficacy; however, its contribution to proteostasis imbalance is relatively limited, as cells possess other robust proteostasis regulatory networks. Consequently, targeting the autophagy-lysosome system is often employed as a compensatory mechanism in conjunction with other proteotoxic inducers (e.g., proteasome inhibitors, ER stressors, and HSR inhibitors) to further exacerbate proteotoxicity or overcome drug resistance. Hassan AMIA systematically summarized the drugs that inhibit autophagy flux at various stages, including autophagosome initiation, maturation, and lysosomal degradation [231].

Challenge of targeting proteostasis for cancer therapy

As previously noted, maintaining proteostasis in tumor cells results from a multifaceted and multi-pathway regulatory network. Disrupting any single signaling pathway can lead to the activation of tumor cells on other response pathways, particularly in vivo treatments where the tumor microenvironment facilitates tumor cell adaptation to proteotoxic stress. For example, proteasome inhibition can trigger the activation of the UPR, HSR, and autophagy, all of which promote the clearance of misfolded proteins and ultimately reduce proteotoxicity [157, 232]. Therefore, a multi-pathway targeting strategy may enhance the efficacy of proteostasis-targeted therapies in cancer treatment. Indeed, both preclinical studies and clinical trials have explored this approach, such as combining proteasome inhibitors with HSP90 inhibitors [234, 235, NCT01270399], autophagy inhibitors [235, 236], and IRE1 inhibitors [237,238,239]. These multi-pathway strategies significantly exacerbate proteotoxic cell death in tumor cells, potentially representing a breakthrough in proteostasis-targeted cancer therapy.

Moreover, tumor cells display diverse responses to proteotoxic stress. For example, autophagy activation provides protection in some cancers, such as MM [240], prostate cancer [241], CRC [242], and osteosarcoma cells [243]. In contrast, in others—such as neuroblastoma [244], melanoma [245], breast cancer [245]—autophagy offers minimal protection against proteasome inhibition. Additionally, the multiple arms of the UPR signaling offer a wide range of intervention targets for UPR modulation, but they also introduce complexity in regulating tumor cell fate. For example, in TP53 mutant ovarian cancer treated with AZD1775 (an inhibitor of the G2/M checkpoint mediator WEE1), PERK activation can trigger CHOP-mediated apoptotic signaling, while IRE1α-induced splicing of XBP1 represses apoptosis [246]. In lymphoma cells under ER stress, inhibiting IRE1α enhances cell death, which can be mitigated by targeting PERK, due to PERK-dependent autophagic degradation of eIF2α, which controls protein translation [247]. Therefore, strategies targeting proteostasis in cancer therapy should be tailored based on the specific functional roles of signaling pathways within tumor cells.

Although various proteotoxic inducers have been developed based on multiple perspectives of the proteostasis network (Table 1), and preclinical studies have demonstrated promising antitumor effects, the currently approved clinical applications of proteotoxic stressors remain limited, primarily focused on proteasome inhibitors. This is insufficient to address the diversity of the tumor proteostasis network in clinical treatments. Furthermore, proteasome inhibitors are largely restricted to the treatment of hematological malignancies, with limited efficacy against solid tumors, despite nearly two decades of clinical exploration. Although several proteotoxic inducers are currently undergoing or have completed clinical trials for the treatment of various tumors (Table 2), significant progress is still needed before they can be approved for clinical application. Thus, the development of diverse proteotoxic inducers suitable for clinical use remains a focal point for future research, with an emphasis on drug target specificity, low toxicity, and favorable pharmacokinetics.

Table 2 Main clinical trials of proteotoxic inducers

Full size table

Moreover, proteostasis is essential for the survival and growth of all cells, including both normal and tumor cells. Traditional administration of proteotoxic inducers, while disrupting tumor cell proteostasis, inevitably affects the proteostasis of normal cells, leading to potential side effects in targeted proteostasis cancer therapies. Therefore, developing drugs that specifically target tumor tissues is critical in future preclinical studies and clinical trials. On the one hand, the unique regulatory mechanisms of proteostasis in tumor cells provide precise therapeutic targets; on the other hand, accurate drug delivery to tumor tissues enhances therapeutic efficacy and reduces side effects. For example, nanoparticle formulations containing metal ions, such as ZnO-NPs [248] and AgNPs [249], as well as nanoparticle delivery systems with proteotoxic inducers like CLANTAK-243 [250], BCMA-BTZ-NPs [251], FOL-MSN-BTZ [252], and DPA-G5-PEG-cRGD/BTZ [253], can significantly improve drug targeting to tumor tissues. Additionally, combining nanoparticle therapies with thermal dynamic therapy and photothermal therapy could induce heat shock-driven proteotoxic stress, further enhancing tumor cell proteotoxicity.

Targetable vulnerability in proteostasis-targeted tumor therapy

During proteostasis-targeted cancer therapy, tumor cells can circumvent drug-induced proteotoxicity by activating key factors or signaling pathways, thereby reducing therapeutic efficacy or promoting resistance to proteotoxic inducers (Table 3). Targeting these regulators offers a promising strategy to enhance tumor sensitivity to proteotoxic stress (Table 3). Additionally, certain intrinsic features of tumor cells that drive malignant progression may fortify the proteostasis network critical for tumor growth, thereby generating exploitable vulnerabilities for proteostasis-based therapeutic approaches (Fig. 3).

Table 3 Proteins/pathways regulating tumor cell sensitivity to proteotoxic stress

Full size table

Protein synthesis

Elevated protein synthesis levels play a pivotal role in the survival of tumor cells, simultaneously making them more sensitive to proteotoxic stressors. Tumor cells characterized by high protein synthesis rates, such as those in myeloma, breast cancer, melanoma, and GBM, are particularly sensitive to proteotoxic inducers [6,7,8]. Conversely, reduced protein synthesis can diminish tumor cell responsiveness to proteotoxic stressors, potentially contributing to drug resistance. For instance, Chui et al. demonstrated that ovarian cancer spheroids downregulate mTORC1, which enhances protein synthesis through the phosphorylation of translation repressors Like 4E-BP1 and translation promoters like S6K. This reduction in translation confers resistance to Bortezomib [254].

Furthermore, several oncogenic signaling pathways, including the mTOR, MYC, and MAPK pathways, enhance protein synthesis. While these pathways drive tumor cell growth and metastasis, they also create favorable conditions for sensitizing tumors to proteostasis-targeting therapies. PTEN (phosphatase and tensin homolog deleted on chromosome ten), a tumor suppressor gene whose mutation or deletion drives tumorigenesis and malignant transformation, negatively regulates the PI3K-AKT and mTORC1 signaling pathways [255]. Loss of PTEN leads to heightened mTORC1 activation and increased protein synthesis. Preclinical studies have confirmed that PTEN deficiency sensitizes high-grade serous ovarian cancer [254, 256], cholangiocarcinoma [257], gallbladder cancer [258], and GBM [259] cells to proteasome inhibitors. Clinical trials assessing the efficacy of Bortezomib in treating PTEN-deficient solid tumors are currently underway (NCT03345303, NCT06029998), which may lead to breakthroughs in treating solid tumors with proteasome inhibitors. EGFR-mediated signaling plays a significant role in enhancing the mTOR pathway in tumor cells. Research has shown that in EGFR + or HER2 + breast cancer cells, proteotoxic inducers like cyclosporine A (CsA), a peptidyl-prolyl isomerase inhibitor, and VCP/p97 inhibitors can induce protein synthesis-dependent proteotoxic cell death [260, 261].

MYC, a crucial oncogenic driver and enhancer of protein synthesis, activates transcription across all three RNA polymerases, increasing protein synthesis and ribosome biogenesis [262]. In normal epithelial cells, highly activated MYC induces cellular proteotoxicity, whereas in transformed tumor cells, MYC-mediated proteotoxicity is mitigated by the proteotoxic stress response [86, 263]. This duality renders MYC-overexpressing tumor cells particularly sensitive to proteotoxic inducers. Disrupting their proteostasis network can inhibit tumor growth [86, 263, 264]. Interestingly, research by Feven Tameire and colleagues demonstrated that MYC activation suppresses the mTORC1-4E-BP1 signaling pathway in an ATF4-dependent manner, subsequently reducing protein synthesis rates and alleviating proteotoxic stress in tumor cells [265]. Thus, MYC’s regulation of protein synthesis in tumor cells may play a dual role, suggesting that proteostasis-targeting anti-cancer strategies in MYC-driven tumors should carefully consider these mechanisms.

The MAPK signaling pathway is also known to enhance protein synthesis in tumor cells. For instance, in KRAS (Kirsten ratsarcoma viral oncogene homolog) mutant pancreatic epithelial cells, protein synthesis levels are significantly elevated, accompanied by increased autophagy, which may help process misfolded proteins generated during protein synthesis, thereby mitigating or eliminating proteotoxicity [266], suggesting KRAS mutant tumor cells may be sensitive to proteotoxic inducer. However, clinical trials evaluating the efficacy of proteasome inhibitors in KRAS G12D-mutant lung cancers have yielded negative results [267]. A potential explanation for this may be that KRAS signaling maintains proteostasis through multiple pathways, making single-agent proteasome inhibition insufficient to induce proteotoxic cell death in these tumors. Future research elucidating the molecular mechanisms by which the MAPK signaling pathway reshapes tumor cell proteostasis may uncover additional targets and strategies for treating MAPK-driven tumors.

Proteasomal activity

Active proteasome highlights the tumor cells’ dependency on elevated proteasome levels, making them particularly sensitive to targeted proteostasis interventions. Therefore, targeting proteostasis presents a promising therapeutic strategy for tumor cells with high proteasome levels, especially in specific solid tumors such as breast cancer [51], melanoma [268], GBM [269], and CRC [49]. Moreover, inducing high proteasome expression or enhancing proteasomal activity in tumor cells could sensitize these cells to proteotoxic inducers. Antonia Busse and colleagues analyzed the relationship between tumor cell sensitivity to proteasome inhibitors and proteasome activity, and found that high expression of proteasome subunits, particularly immunoproteasome subunits, renders tumor cells more sensitive to proteasome inhibitors [270]. Additionally, Nuclear Factor E2-related factor 2 (NRF2), a key regulator of the cellular ROS response, translocates to the nucleus during oxidative stress and promotes the expression of antioxidant enzymes by binding to the Antioxidant Response Element (ARE) [271]. Arlt et al. found that high NRF2 expression in CRC promotes the expression of proteasome subunits PSMD4 and PSMA5, thereby enhancing proteasome activity in tumor cells [49]. Since NRF2 plays a crucial role in drug resistance, this finding suggests that targeting proteostasis in NRF2-activated cells may offer a strategy for overcoming drug resistance in cancer therapy.

It is important to recognize that high proteasome activity can also contribute to tumor cell resistance to proteasome inhibitors. For example, Fazal Shirazi et al. demonstrated that in MM cells, activation of the MAPK signaling pathway, including mutations in KRAS, NRAS, and BRAF, leads to increased expression of proteolytic subunits within the proteasome, thereby enhancing proteasome activity and conferring resistance to proteasome inhibitors [272]. The combination of proteasome inhibitors with MAPK pathway inhibitors, such as MEK inhibitors, significantly suppresses the growth of tumors with persistent MAPK pathway activation [272]. Furthermore, as previously mentioned, low proteasome activity may also aid tumor cells in resisting treatment, Such as by desensitizing CSCs to proteotoxic inducers and enabling cell populations with low 26S proteasome activity to resist radiotherapy [52, 273]. Future research elucidating the regulatory mechanisms governing proteasome levels and activity in tumor cells will be crucial for effectively targeting proteostasis to inhibit tumor growth.

Oncogenic mutant p53

Oncogenic mutant p53 is a significant driver of tumor progression and therapeutic failure. Several studies have demonstrated that mutant p53 facilitates the adaptation of tumor cells to proteotoxic stress [274,275,276]. Mechanistically, mutant p53 enhances the transcriptional regulation of HSPs by promoting the activity of HSF1, thereby amplifying the HSR to mitigate proteotoxic stress [274]. Additionally, mutant p53 upregulates ENTPD5 (ectonucleoside triphosphate diphosphohydrolase 5), an enzyme that aids in the proper folding of N-glycosylated proteins, promoting their maturation and secretion in the ER and reducing the accumulation of misfolded proteins within the ER [277]. Furthermore, mutant p53 interacts with NRF2 to upregulate the expression of proteasome subunits, thereby increasing both the quantity and activity of the proteasome in tumor cells [275, 276]. This reinforcement of the proteostasis regulatory network by mutant p53 not only increases the tumor cells’ dependence on proteostasis but also may render them more sensitive to proteotoxic inducers. Chougoni et al. found that NSCLC cells expressing oncogenic p53, which exhibit heightened proteasome activity, are more intolerant to Bortezomib compared to cells with wild-type p53 [276]. Ramona et al. demonstrated through in vivo and in vitro experiments that, in CRC cells, wild-type p53 inhibits the cells’ HSR [278]. Mechanistically, wild-type p53 activates cyclin-dependent kinase inhibitor 1 A (CDKN1A/p21), which in turn inhibits MLK3 (mixed Lineage kinase 3), a mediator that enhances the MAPK stress pathway and activates HSF1-mediated HSR. In heterozygous TP53 tumor cells, the reduction of wild-type p53 leads to the activation of HSR and the remodeling of proteostasis, driving tumorigenesis [278]. Recently, this team showed that Idasanutlin, a clinically relevant p53 activator, can synergistically enhance the antitumor effects of HSP90 inhibitors by suppressing HSF1-mediated HSR activation in p53-proficient CRC cells, both in cultured cells and patient-derived organoids [279]. Therefore, while oncogenic mutant p53 drives tumorigenesis and growth, it simultaneously offers a therapeutic avenue for targeting proteostasis, providing a novel breakthrough for the treatment of tumors driven by oncogenic mutant p53.

Targeting proteostasis to overcome tumor drug resistance

Drug resistance represents a significant challenge in tumor therapy, limiting the efficacy of various therapeutic agents, including chemotherapy and targeted therapies, and hindering their ability to control disease progression. While inducing proteotoxicity can damage tumor cells, increasing opportunities for strategies aimed at promoting tumor cell death, tumor cells can also remodel proteostasis during drug treatment to trigger or enhance their resistance to drugs. Therefore, targeting proteostasis presents a promising therapeutic strategy to overcome tumor drug resistance (Fig. 3).

Targeting proteostasis to overcome resistance to tumor chemotherapy

Chemotherapeutic agents, such as platinum-based drugs, paclitaxel, gemcitabine, and docetaxel, frequently disrupt proteostasis in tumor cells, resulting in impaired protein folding, increased production of misfolded proteins, and protein oxidation [309, 310]. In response, tumor cells enhance the regulation of their proteostasis network to alleviate or adapt to proteotoxic stress, thus promoting resistance to these drugs. Over the past few decades, research has shown that activation of UPR signaling pathways is a key driver of drug resistance in tumor cells, including those in hematological malignancies and solid tumors [309]. As previously discussed, UPR signaling can activate multiple survival pathways, enhancing biological processes in tumor cells, such as DNA damage repair, removal of damaged proteins and organelles, and reduced drug accumulation, all of which contribute to drug resistance [161, 309]. Inhibition of UPR signaling has been shown to sensitize tumor cells to chemotherapy or reverse therapy resistance in various tumor types. This concept has been extensively explored and summarized in the literatures [161, 309,310,311,312,313].

Moreover, the activation of the HSR has also been associated with resistance to various chemotherapy agents [314,315,316,317]. On the one hand, HSR activation promotes the proper folding of misfolded proteins during chemotherapy, alleviating proteotoxic stress [314, 315]. On the other hand, HSR signaling can enhance the expression of proteins involved in drug efflux, Such as multidrug resistance 1 (MDR1) and ATP-binding cassette (ABC) transporters, which increase cellular resistance to chemotherapy by reducing drug concentrations within tumor cells [318,319,320,321,322]. Preclinical studies have demonstrated that inhibiting HSR signaling can overcome tumor cell resistance to chemotherapy. For example, in ovarian cancer and pancreatic ductal adenocarcinoma, both in vivo and in vitro studies have shown that inhibiting HSP90 significantly enhances tumor cell sensitivity to platinum-based drugs [323,324,325,326]. In breast cancer cells, HSF1 knockdown has been shown to increase tumor cell sensitivity to carboplatin, a process thought to involve the prevention of HSF1-induced autophagy [327].

Similarly, as a critical regulator of proteostasis, targeting the UPS has been widely investigated as a therapeutic strategy to reverse tumor drug resistance, with promising results in preclinical studies. However, clinically approved proteasome inhibitors, when combined with chemotherapy, remain limited in both hematological malignancies and solid tumors [328,329,330,331,332]. Despite numerous clinical trials, most have been halted due to severe toxic side effects or failed to demonstrate significant therapeutic efficacy. Consequently, future research should focus on developing novel, effective, and low-toxicity proteotoxic inducers, particularly those suitable for clinical application, to further the study of targeting proteostasis as a strategy to overcome drug resistance in tumor chemotherapy.

Targeting proteostasis to overcome resistance to tumor-targeted therapy

Targeted therapy has become a cornerstone of cancer treatment, supported by detailed insights into the molecular mechanisms of tumorigenesis and progression. Nevertheless, the emergence of drug resistance remains a major limitation to its sustained efficacy. Growing evidence indicates that reprogramming of cellular proteostasis is a critical driver of resistance to targeted agents, making the disruption or reversal of proteostasis a promising strategy to overcome therapeutic failure.

Among key oncogenic drivers, KRAS mutations lead to persistent activation of the MAPK pathway, contributing to the development of multiple malignancies, including pancreatic cancer, CRC, and NSCLC. Although long considered “undruggable,” recent advances have led to the development and clinical validation of KRAS mutation-specific inhibitors, such as KRAS G12C inhibitors sotorasib and adagrasib and KRAS K12D inhibitor MRTX1133. Chen et al. revealed that the efficacy of KRAS inhibition is closely linked to proteostasis dynamics, identifying proteostasis remodeling as a principal mechanism of resistance to KRAS and MAPK pathway inhibitors [333]. Mechanistically, suppression of the KRAS-MAPK axis triggers compensatory activation of RTK-AKT and ERK pathways, culminating in the re-phosphorylation of IRE1α and enhanced cellular adaptation to proteotoxic stress [333]. In vivo studies using cell derived xenograft (CDX) and patient-derived xenografts (PDX) models confirmed that the IRE1α inhibitor MKC8866 (Orin1001) effectively reverses resistance to KRAS-MAPK inhibitors in KRAS-mutant tumors, showing robust antitumor efficacy [333]. In parallel, Zhou et al. developed HRS-4642, a KRAS G12D-specific inhibitor, and demonstrated that co-administration with the proteasome inhibitor Carfilzomib synergistically enhanced its antitumor activity [334]. This effect was attributed to inhibition of NOTCH4 signaling and upregulation of the interferon-α response, resulting in remodeling of the tumor immune microenvironment [334]. However, the precise contribution of proteotoxic stress to this synergy warrants further investigation. BRAF (B-Raf proto-oncogene serine/threonine kinase), another pivotal node in the RAS-MAPK pathway, is frequently mutated in melanoma, thyroid cancer, CRC, and NSCLC. Although BRAF inhibitors such as dabrafenib and vemurafenib show initial efficacy in BRAF V600E-positive melanoma, resistance frequently develops [335]. Qin et al. found that in PTEN-deficient, BRAFi (BRAF inhibitor)-resistant melanoma cells, upregulation of PERK conferred resistance, which could be reversed by the PERK inhibitor GSK2606414 [336]. Notably, this resistance mechanism was absent in PTEN wild-type cells [336]. Given its function in suppressing protein synthesis under stress, PERK likely supports cell survival in PTEN-deficient tumors by alleviating proteotoxic stress caused by increased translational demand. Moreover, additional proteotoxic inducers—such as mefloquine [337], KU758 [338], and b-AP15 [339]—have demonstrated efficacy in restoring sensitivity to BRAFi in BRAF V600E-mutant melanoma by exacerbating proteotoxic stress.

Aberrant activation of receptor tyrosine kinases (RTKs), including EGFR, PDGFR, FGFR, VEGFR, and ALK (anaplastic lymphoma kinase), plays a critical role in tumorigenesis, making RTKs prime targets in cancer therapy. Wang et al. showed that Bortezomib enhances the efficacy of bevacizumab, a humanized anti-VEGF monoclonal antibody, in CDX tumor models [340]. Additionally, breast cancer cells overexpressing HER2/EGFR exhibit sensitivity to proteotoxic inducers, indicating that proteostasis targeting may mitigate RTK inhibitor resistance [260, 263]. Studies also confirm that proteotoxic inducers overcome resistance to Lapatinib, a dual HER2/EGFR kinase inhibitor, in HER2/EGFR-overexpressing breast cancer cells [341]. In NSCLC, 3%−5% of patients have ALK gene rearrangements, making ALK inhibitors like Alectinib the primary treatment [342]. Tanimoto et al. found TP53 mutations increase resistance to Alectinib in ALK-rearranged NSCLC cells, but the proteasome inhibitor ixazomib reverses this resistance by upregulating NOXA, triggering apoptosis through sequestration of Mcl-1 [343]. Sorafenib, a multitargeted kinase inhibitor, inhibits tumor proliferation and angiogenesis by targeting the RAF/MEK/ERK pathway and VEGFR/PDGFR signaling. It is used for HCC and advanced renal cancer. Elevated autophagy has been linked to sorafenib resistance [344, 345]. Gavini et al. demonstrated that verteporfin sensitizes HCC cells to sorafenib by disrupting lysosomal activity and inducing proteotoxicity, independent of YAP1, a well-known target of verteporfin, suggesting that autophagy-mediated proteostasis remodeling drives HCC resistance to sorafenib [346]. Moreover, proteostasis modulation has been shown to enhance the effects of inhibitors targeting downstream RTK signaling pathways. For example, the combination of HSF1 inhibitor KRIBB11 and AKT inhibitor MK-2206 synergistically eliminates breast cancer cells and cancer stem cells [347].

In conclusion, proteostasis remodeling is pivotal in resistance to targeted cancer therapies, positioning proteostasis modulation as a promising strategy to overcome resistance. Future research should focus on developing new proteotoxic inducers and uncovering novel molecular mechanisms of proteostasis remodeling that contribute to drug resistance. Investigating regulatory mechanisms of proteostasis, such as protein synthesis and secretion, will provide insights into their role in drug resistance and facilitate the development of new therapeutic strategies to overcome resistance to targeted cancer therapies.

Targeting proteostasis to enhance tumor immunotherapy

Tumor immunity plays a pivotal role in determining cancer outcomes in patients. Tumor immunotherapy, including immune checkpoint inhibitors, adoptive cell therapy, and tumor vaccines, represents a new generation of cancer treatments with promising clinical prospects. Proteotoxic stress-induced cell death has the potential to activate anti-tumor immune responses. As discussed earlier, severe proteotoxic stress can induce various forms of cell death in tumor cells, leading to immunogenic cell death (ICD), in which tumor cells transition from non-immunogenic to immunogenic, thereby initiating anti-tumor immunity. During ICD, danger-associated molecular patterns (DAMPs), Such as calreticulin, high-mobility group box 1 (HMGB1), HSPs, and ATP, are released from tumor cells and stimulate immune cells, including dendritic cells (DCs), T cells, and macrophages [348]. Studies have demonstrated that targeting proteostasis influences the release of DAMPs from tumor cells and the activation of anti-tumor immunity. For example, in melanoma cells, gene knockout or pharmacological inhibition of PERK triggers SEC61β-induced paraptosis, enhancing ICD and promoting type I interferon production in intra-tumoral DCs [349]. This induces tumor trafficking and differentiation of monocyte precursors into Ly6C + CD103 + monocytic-lineage inflammatory DCs, further boosting T cell immunity [349]. Interestingly, while proteasome-dependent protein degradation is essential for antigen presentation via major histocompatibility complexes and subsequent immune cell activation, increasing evidence suggests that targeting the UPS can also activate ICD in tumor cells. For instance, Benvenuto et al. demonstrated that in mice transplanted with head and neck cancer (HNC) cells, Bortezomib enhanced immune cell infiltration (e.g., CD4 + and CD8 + T cells, NK cells, B lymphocytes, and macrophages) into tumor tissues, thus modulating the tumor microenvironment [350]. Additionally, Wang et al. showed that nanoparticle-delivered TAK-243 promotes the release of tumor antigens, which are engulfed by DCs, activating DC maturation and homing to tumor-draining lymph nodes [250]. There, DCs present tumor antigens to T cells, triggering robust T cell responses against the tumor [250]. Maione et al. recently demonstrated that in a BRAF-mutant mouse model of CRC, intravenous Carfilzomib inhibited tumor growth by promoting the emission of immunostimulatory signals, such as calreticulin translocation and HMGB1 secretion, leading to ICD modulation and the activation of cytotoxic T cells and NK cells [351]. These findings suggest that targeting proteostasis to induce proteotoxicity in tumor cells holds promise as a strategy to activate ICD and enhance anti-tumor immunity.

In addition to the impact of proteotoxic stress within tumor cells on anti-tumor immune responses, proteotoxic stress in immune cells also significantly influences their activation, tumor tissue infiltration, and other anti-tumor behaviors. A prominent focus has been the effect of UPR signaling on macrophage polarization. Macrophages within tumor tissues exhibit an activated UPR state, where the IRE1 branch promotes the nonautonomous polarization of Macrophages, including the upregulation of Arginase 1, interleukin 23 (IL-23), IL-6, and the surface expression of PD-L1 and CD86, thereby inhibiting anti-tumor immunity [352]. Pharmacological inhibition or gene deletion of IRE1α reduces macrophage polarization and the expression of PD-L1 and CD86, subsequently extending the survival of tumor-bearing animals [352]. Moreover, Ma et al. found that in lung cancer tissues from the offspring of mice exposed to prenatal inflammation, tumor-associated macrophages displayed activated UPR, M2-like polarization, and PD-L1 expression [353]. The IRE1α inhibitor KIRA6 was shown to reverse the M2-like polarization of tumor-associated macrophages (TAMs) and reduce tumor metastasis [353]. Interestingly, other studies have indicated that ER stress can inhibit M2 polarization in macrophages. Zhou et al. employed both in vivo and in vitro studies to demonstrate that proteasome inhibitors, such as Carfilzomib, can induce ER stress, activating the IRE1a-TRAF2 signaling pathway dependent on NF-κB in macrophages [354]. This activation prompts highly immunosuppressive M2 macrophages to express M1 macrophage cytokines, resulting in the reprogramming of TAMs into immunostimulatory M1 cells [354]. This dual function may stem from differences in UPR triggers and the severity of ER stress, as varying induction methods and extents of ER stress can lead to distinct cellular fates within tumor cells. Future research aimed at elucidating the molecular networks regulating macrophage polarization through UPR/ER stress will be crucial for the targeted activation of macrophages’ anti-tumor functions. Additionally, Nikotina et al. discovered that the activation of HSF1 in macrophages plays a critical role in macrophage-mediated tumor drug resistance. Inhibition of HSF1 using CL-43 was found to reverse the cytoprotective effects of monocytes or macrophages on tumor cells [355]. This suggests that proteostasis and the HSR may serve as essential regulatory mechanisms of macrophage function, the specific molecular mechanisms of which warrant further investigation in future studies.

The binding of PD-L1 on the surface of tumor cells, DCs and macrophages to PD-1 on T cells induces T cell apoptosis, dysfunction, and exhaustion, thereby facilitating immune evasion of tumor cells [356]. Therefore, targeting the PD-1/PD-L1 pathway has emerged as an important strategy in tumor immunotherapy. Currently, various inhibitors and antibodies targeting PD-1/PD-L1 are used in clinical anti-tumor treatments, including Nivolumab, Pembrolizumab, Atezolizumab, and Durvalumab. The impact of targeting proteostasis on anti-PD-1 or anti-PD-L1 tumor immunotherapy is notably diverse. On one hand, the UPS and ALP can enhance the anti-tumor effects of T cells by promoting the degradation of PD-1/PD-L1 proteins. From this perspective, inhibition of the UPS or ALP would stabilize PD-1/PD-L1 proteins, thereby suppressing anti-tumor immunity. On the other hand, proteotoxic inducers have been reported to affect the efficacy of anti-PD-1 or anti-PD-L1 tumor treatments. For instance, HSP90 inhibitors have been shown to enhance the anti-tumor effects of anti-PD-L1 in colorectal, melanoma, and pancreatic cancers by reducing the expression of PD-L1 on tumor cell surfaces and upregulating the expression of interferon response genes [357,358,359,360]. In breast cancer cells, it has been discovered that PIM2 (Pim-2 proto-oncogene serine/threonine kinase), an oncogene highly expressed in many malignancies, can promote PD-L1 expression by phosphorylating HSF1 at Thr120, which facilitates PD-L1 expression by binding to its promoter, suggesting that targeting the PIM2-HSF1 pathway may increase anti-tumor immunity [361]. Moreover, the UPR signaling pathways have also been reported to regulate the expression of PD-L1 in tumor cells and immune cells. Yuan et al. reported that ER stress in HNC cells can promote the secretion of PD-L1 via exosomes and enhance macrophage uptake of PD-L1, which in turn promotes M2 macrophage polarization [362]. In triple-negative breast cancer cells, GRP78 stabilizes PD-L1 by binding to it, and ER stress can induce the upregulation of PD-L1 expression [363]. Therefore, targeting the UPR/ER stress pathways represents a potential strategy for reducing PD-L1 expression and sensitizing tumor therapies. These findings suggest that precise and selective targeting of proteostasis could also serve as a strategy to enhance anti-PD-1- or anti-PD-L1-associated tumor immunotherapy.

In summary, given the critical regulatory role of the proteostasis network in tumor antigen presentation, immune cell activation, and inhibition, targeting proteostasis is a promising strategy to augment tumor immunotherapy. However, there is currently no established combinatorial treatment strategy available for clinical application, primarily due to the limited availability of clinically applicable proteostasis-targeting drugs and the unclear molecular mechanisms by which proteotoxic stress regulates tumor immunity. Future research should focus on developing new proteotoxic inducers while elucidating the roles of proteotoxic stress in tumor immunity, particularly in tumor cells that are sensitive to proteotoxicity, such as those with high aneuploidy or vigorous protein synthesis. Additionally, exploring the functions of proteostasis in cell death closely associated with ICD, such as pyroptosis, ferroptosis, and cuproptosis, will also provide new theoretical intervention targets for enhancing anti-tumor immunity by targeting tumor cell proteostasis.

Targeting proteostasis to enhance radiotherapy

Radiotherapy remains a cornerstone treatment for cancer, primarily due to its targeted effects on tumor tissues and relatively low toxicity. However, its clinical application is limited by the challenge of tumor resistance to radiation. In recent years, researchers have explored enhancing tumor sensitivity to radiotherapy through the use of proteotoxic stressors. For example, Bortezomib inhibits radiation-induced activation of NF-κB, increasing apoptosis in CRC and oral cancer cells and reducing cell growth and clonogenic survival [364, 365]. The IRE1α inhibitor Kira8 and the ATF6 inhibitor Ceapin-A7 have been shown to reverse radioresistance in pancreatic cancer cells by blocking the activation of the UPR [366]. Additionally, HSP90 inhibitors, including NXD30001, 17-AAG, and NW457, enhance the radiosensitivity of various tumor cells by impairing the DNA damage response and promoting apoptosis following radiotherapy [230, 367,368,369,370]. Hyperthermia (HT), a modality that sensitizes tumor cells to ionizing radiation, has been used clinically for various cancers, including breast cancer, head and neck tumors, esophageal cancer, gliomas, and ovarian cancer, due to its precision and safety [371]. One key mechanism by which HT sensitizes tumor cells is through protein damage at elevated temperatures, triggering proteotoxic stress and DNA damage. However, the effectiveness of this approach may be diminished by the remodeling of the proteostasis network. Chen et al. utilized a spheroid assay platform to demonstrate that in head and neck squamous cell carcinoma, HT induces the HSR and proteotoxic stress, enhancing tumor cell radioresistance [372]. Future research should focus on investigating the potential of combining proteotoxic stressors, such as HSF1 inhibitors and HSP90 inhibitors, with HT-radiotherapy as a therapeutic strategy to overcome radioresistance and improve cancer treatment outcomes.

Conclusions and future perspectives

The proteostasis network plays a fundamental role in enabling tumor cells to maintain protein homeostasis, adapt to proteotoxic stress, alleviate cellular toxicity, and ultimately facilitate tumor progression and resistance to therapy. As such, targeting proteostasis has garnered increasing attention as a novel anti-cancer strategy, demonstrating promising outcomes in preclinical studies. By disrupting the proteotoxic stress response within tumor cells, it is possible to induce cell death and potentiate the efficacy of various therapeutic modalities, including chemotherapy, targeted therapy, immunotherapy, and radiotherapy.

Despite encouraging preclinical evidence, the clinical translation of proteostasis-targeting strategies remains fraught with challenges. First, the molecular mechanisms governing the remodeling of proteostasis in tumor cells are not yet fully elucidated. The intricate interplay and compensatory relationships among regulatory pathways complicate the induction of proteotoxic cell death through single-target approaches. Second, the repertoire of clinically available agents remains limited—particularly proteasome inhibitors, which exhibit restricted therapeutic applicability and fail to fully address the multifaceted nature of the proteostasis network. Moreover, the risk of off-target toxicity remains a significant concern; developing therapeutic strategies that selectively target tumor cells while minimizing harm to normal tissues is an ongoing challenge. Finally, the emergence of drug resistance further constrains the long-term efficacy and clinical viability of proteostasis-based therapies.

Future research should prioritize the following areas: (1) advancing our understanding of the regulatory architecture and dynamic remodeling of proteostasis networks in tumor cells, with a focus on the crosstalk mechanisms underlying the proteotoxic stress response under various stress conditions and pharmacological interventions; (2) developing next-generation therapeutics with enhanced tumor selectivity and reduced systemic toxicity, alongside innovative drug delivery platforms that enable precise tumor targeting; (3) investigating the role of proteostasis and proteotoxic stress in emerging cell death modalities—such as cuproptosis, ferroptosis, disulfidptosis, and pyroptosis—to clarify their contribution to tumor suppression, particularly in the context of ICD; and (4) elucidating the impact of proteostasis remodeling on the efficacy of other cancer therapies, thereby providing a theoretical basis for rational combination treatment strategies.

In summary, targeting proteostasis represents a compelling therapeutic avenue for inducing tumor cell death and suppressing tumor growth. As our understanding of the molecular underpinnings of the proteotoxic stress response in cancer deepens, and as safer and more effective therapeutic agents and delivery systems are developed, proteostasis-targeting strategies are expected to play an increasingly prominent role in clinical oncology, ultimately improving outcomes for a broader population of cancer patients.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

UPS:: Unfolded protein stress
HSR:: Heat shock response
UPR:: Unfolded protein response
HSPs:: Heat shock proteins
ER:: Endoplasmic reticulum
ERAD:: Endoplasmic reticulum-associated degradation
VCP/p97:: Valosin-containing protein
HSC70:: Heat shock cognate protein 70
ACR:: Autophagic cargo receptors
MEK1/2:: Mitogen-activated protein kinase kinase 1/2
RTKs:: Receptor tyrosine kinases
PI3K:: Phosphoinositide 3-kinase
mTORC1:: Mechanistic target of rapamycin complex 1
AMPK:: AMP-activated protein kinase
IRE1:: Inositol-requiring enzyme 1
XBP1:: X-box binding protein 1
PERK:: Protein kinase r-like endoplasmic reticulum kinase
eIF2α:: Eukaryotic translation initiation factor 2α
ATF4:: Activating transcription factor 4
CHOP:: C/EBP homologous protein
ATF6:: Activating transcription factor 6
TRAIL:: Tumor necrosis factor-related apoptosis-inducing ligand
DR5:: Death receptor 5
TNF-α:: Tumor necrosis factorα
TNFR:: Tumor necrosis factor receptor
NF-kB:: Nuclear factor kB
JNK:: C-Jun N-terminal kinase
BAX:: Bcl-2-associated x protein
BAK:: Bcl-2 antagonist/killer
BOK:: Bcl-2-related oncogene
NOXA:: Phorbol-12-myristate-13-acetate-induced protein 1
BCL-2:: B-cell lymphoma 2
BCL-XL:: B-cell lymphoma-extra large
XIAP:: X-linked Inhibitor of apoptosis protein
ROS:: Reactive oxygen species
HSF:: Heat shock factor
MAPK:: Mitogen-activated protein kinase
CaMKII:: Calcium/calmodulin-dependent protein kinase II
BAG3:: BCL2-associated athanogene 3
HRI:: Hemoglobin regulated inhibitor
ISR:: Integrated stress response
DAMPs:: Damage-associated molecular patterns
DCs:: Dendritic cells
NK cells:: Natural killer cells
ICD:: Immunogenic cell death
PD-L1:: Programmed cell death ligand 1
PD-1:: Programmed death receptor 1
MM:: Multiple myeloma
CRC:: Colorectal cancer
DUBs:: Deubiquitinating enzymes
UBA1:: Ubiquitin-activating enzyme 1
RCC:: Renal cell carcinoma
GBM:: Glioblastoma
AML:: Acute myeloid leukemia
HSP90:: Heat shock protein 90
HSP70:: Heat shock protein 70
PTEN:: Phosphatase and tensin homolog
EGFR:: Epidermal growth factor receptor
NSCLC:: Non-small cell lung cancer
NRF2:: Nuclear factor erythroid 2-related factor 2
GCN2:: General control nonderepressible 2
AKT:: Serine/threonine kinase
HNC:: Head and neck cancer

References

Hipp MS, Kasturi P, Hartl FU. The proteostasis network and its decline in ageing. Nat Rev Mol Cell Biol. 2019;20(7):421–35.
Article CAS PubMed Google Scholar
Verma K, Verma M, Chaphalkar A, Chakraborty K. Recent advances in understanding the role of proteostasis. Fac Rev. 2021;10:72.
Article CAS PubMed PubMed Central Google Scholar
Díaz-Villanueva JF, Díaz-Molina R, García-González V. Protein folding and mechanisms of proteostasis. Int J Mol Sci. 2015;16(8):17193–230.
Article PubMed PubMed Central Google Scholar
Kurtishi A, Rosen B, Patil KS, Alves GW, Møller SG. Cellular proteostasis in neurodegeneration. Mol Neurobiol. 2019;56(5):3676–89.
Article CAS PubMed Google Scholar
Oakes SA. Endoplasmic reticulum proteostasis: a key checkpoint in cancer. Am J Physiol Cell Physiol. 2017;312(2):C93–102.
Article PubMed Google Scholar
Dai C, Sampson SB. HSF1: guardian of proteostasis in cancer. Trends Cell Biol. 2016;26(1):17–28.
Article CAS PubMed Google Scholar
Bastola P, Oien DB, Cooley M, Chien J. Emerging cancer therapeutic targets in protein homeostasis. AAPS J. 2018;20(6):94.
Article PubMed Google Scholar
Guang MHZ, Kavanagh EL, Dunne LP, et al. Targeting Proteotoxic Stress in Cancer: A Review of the Role that Protein Quality Control Pathways Play in Oncogenesis. Cancers (Basel). 2019;11(1):66.
Anisimova AS, Alexandrov AI, Makarova NE, Gladyshev VN, Dmitriev SE. Protein synthesis and quality control in aging. Aging (Albany NY). 2018;10(12):4269–88.
Article CAS PubMed Google Scholar
Dobson CM. Protein folding and misfolding. Nature. 2003;426(6968):884–90.
Article CAS PubMed Google Scholar
Kim YE, Hipp MS, Bracher A, Hayer-Hartl M, Hartl FU. Molecular chaperone functions in protein folding and proteostasis. Annu Rev Biochem. 2013;82:323–55.
Article CAS PubMed Google Scholar
Adams J. The proteasome: structure, function, and role in the cell. Cancer Treat Rev. 2003;29(Suppl 1):3–9.
Article CAS PubMed Google Scholar
Mao Y. Structure, dynamics and function of the 26S proteasome. Subcell Biochem. 2021;96:1–151.
Article CAS PubMed Google Scholar
Erales J, Coffino P. Ubiquitin-independent proteasomal degradation. Biochim Biophys Acta. 2014;1843(1):216–21.
Article CAS PubMed Google Scholar
Davies KJ. Degradation of oxidized proteins by the 20S proteasome. Biochimie. 2001;83(3–4):301–10.
Article CAS PubMed Google Scholar
Wen P, Sun Y, Jiang TX, Qiu XB. PA200-mediated proteasomal protein degradation and regulation of cellular senescence. Int J Mol Sci. 2024;25(11):5637.
Article CAS PubMed PubMed Central Google Scholar
Cascio P. PA28αβ: the enigmatic magic ring of the proteasome? Biomolecules. 2014;4(2):566–84.
Article PubMed PubMed Central Google Scholar
Cascio P. Pa28γ: new insights on an ancient proteasome activator. Biomolecules. 2021;11(2):228.
Article CAS PubMed PubMed Central Google Scholar
Varshavsky A. The ubiquitin system, autophagy, and regulated protein degradation. Annu Rev Biochem. 2017;86:123–8.
Article CAS PubMed Google Scholar
Stolz A, Ernst A, Dikic I. Cargo recognition and trafficking in selective autophagy. Nat Cell Biol. 2014;16(6):495–501.
Article CAS PubMed Google Scholar
Cuervo AM, Wong E. Chaperone-mediated autophagy: roles in disease and aging. Cell Res. 2014;24(1):92–104.
Article CAS PubMed Google Scholar
Bonnington KE, Kuehn MJ. Protein selection and export via outer membrane vesicles. Biochim Biophys Acta. 2014;1843(8):1612–9.
Article CAS PubMed Google Scholar
Malhotra V. The pathways of secretory cargo export at the endoplasmic reticulum. Nat Commun. 2025;16(1):2138.
Article CAS PubMed PubMed Central Google Scholar
Pourdehnad M, Truitt ML, Siddiqi IN, Ducker GS, Shokat KM, Ruggero D. Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. Proc Natl Acad Sci U S A. 2013;110(29):11988–93.
Article CAS PubMed PubMed Central Google Scholar
Grzmil M, Huber RM, Hess D, et al. MNK1 pathway activity maintains protein synthesis in rapalog-treated gliomas. J Clin Invest. 2014;124(2):742–54.
Article CAS PubMed PubMed Central Google Scholar
Bahar ME, Kim HJ, Kim DR. Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies. Signal Transduct Target Ther. 2023;8(1):455.
Article CAS PubMed PubMed Central Google Scholar
Fu Y, Jung AW, Torne RV, et al. Pan-cancer computational histopathology reveals mutations, tumor composition and prognosis. Nat Cancer. 2020;1(8):800–10.
Article CAS PubMed Google Scholar
Gordon DJ, Resio B, Pellman D. Causes and consequences of aneuploidy in cancer. Nat Rev Genet. 2012;13(3):189–203.
Article CAS PubMed Google Scholar
Muhammad B, Parks LG, Komurov K, Privette Vinnedge LM. Defective transcription elongation in human cancers imposes targetable proteotoxic vulnerability. Transl Oncol. 2022;16.
Feldman DE, Chauhan V, Koong AC. The unfolded protein response: a novel component of the hypoxic stress response in tumors. Mol Cancer Res. 2005;3(11):597–605.
Article CAS PubMed Google Scholar
Sannino S, Manuel AM, Shang C, Wendell SG, Wipf P, Brodsky JL. Non-Essential Amino Acid Availability Influences Proteostasis and Breast Cancer Cell Survival During Proteotoxic Stress. Mol Cancer Res. 2023;21(7):675–690.
Singh MK, Shin Y, Ju S, et al. Heat shock response and heat shock proteins: current understanding and future opportunities in human diseases. Int J Mol Sci. 2024;25(8):4209.
Article CAS PubMed PubMed Central Google Scholar
Pirkkala L, Nykänen P, Sistonen L. Roles of the heat shock transcription factors in regulation of the heat shock response and beyond. FASEB J. 2001;15(7):1118–31.
Article CAS PubMed Google Scholar
Nakai A. Molecular basis of HSF regulation. Nat Struct Mol Biol. 2016;23(2):93–5.
Article CAS PubMed Google Scholar
Santagata S, Hu R, Lin NU, et al. High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer. Proc Natl Acad Sci U S A. 2011;108(45):18378–83.
Article CAS PubMed PubMed Central Google Scholar
Liu Y, Shi Q, Su Y, Chen Z, He X. Heat shock transcription factor 1 facilitates liver cancer progression by driving super-enhancer-mediated transcription of MYCN. Cancer Med. 2024;13(17):e70157.
Article CAS PubMed PubMed Central Google Scholar
Cui J, Tian H, Chen G. Upregulation of nuclear heat shock factor 1 contributes to tumor angiogenesis and poor survival in patients with Non-Small cell lung cancer. Ann Thorac Surg. 2015;100(2):465–72.
Article PubMed Google Scholar
Björk JK, Ahonen I, Mirtti T, et al. Increased HSF1 expression predicts shorter disease-specific survival of prostate cancer patients following radical prostatectomy. Oncotarget. 2018;9(58):31200–13.
Article PubMed PubMed Central Google Scholar
Liang W, Liao Y, Zhang J, et al. Heat shock factor 1 inhibits the mitochondrial apoptosis pathway by regulating second mitochondria-derived activator of caspase to promote pancreatic tumorigenesis. J Exp Clin Cancer Res. 2017;36(1):64.
Article PubMed PubMed Central Google Scholar
Chou SD, Prince T, Gong J, Calderwood SK. mTOR is essential for the proteotoxic stress response, HSF1 activation and heat shock protein synthesis. PLoS One. 2012;7(6):e39679.
Lu WC, Omari R, Ray H, et al. AKT1 mediates multiple phosphorylation events that functionally promote HSF1 activation. FEBS J. 2022;289(13):3876–93.
Article CAS PubMed PubMed Central Google Scholar
Tang Z, Dai S, He Y, et al. MEK guards proteome stability and inhibits tumor-suppressive amyloidogenesis via HSF1. Cell. 2015;160(4):729–44.
Article CAS PubMed PubMed Central Google Scholar
Finka A, Goloubinoff P. Proteomic data from human cell cultures refine mechanisms of chaperone-mediated protein homeostasis. Cell Stress Chaperones. 2013;18(5):591–605.
Article CAS PubMed PubMed Central Google Scholar
Park J, Cho J, Song EJ. Ubiquitin-proteasome system (UPS) as a target for anticancer treatment. Arch Pharm Res. 2020;43(11):1144–61.
Article CAS PubMed PubMed Central Google Scholar
Ikeda F, Dikic I. Atypical ubiquitin chains: new molecular signals. EMBO Rep. 2008;9(6):536–42.
Article CAS PubMed PubMed Central Google Scholar
Pickart CM. Mechanisms underlying ubiquitination. Annu Rev Biochem. 2001;70:503–33.
Article CAS PubMed Google Scholar
Clague MJ, Coulson JM, Urbé S. Cellular functions of the DUBs. J Cell Sci. 2012;125(Pt 2):277–86.
Article CAS PubMed Google Scholar
Gandolfi S, Laubach JP, Hideshima T, Chauhan D, Anderson KC, Richardson PG. The proteasome and proteasome inhibitors in multiple myeloma. Cancer Metastasis Rev. 2017;36(4):561–84.
Article CAS PubMed Google Scholar
Arlt A, Bauer I, Schafmayer C, et al. Increased proteasome subunit protein expression and proteasome activity in colon cancer relate to an enhanced activation of nuclear factor E2-related factor 2 (Nrf2). Oncogene. 2009;28(45):3983–96.
Article CAS PubMed Google Scholar
Ivanova EV, Kondakova IV, Spirina LV, Afanas’ev SG, Avgustinovich AV, Cheremisina OV. Chymotrypsin-like activity of proteasomes and total calpain activity in gastric and colorectal cancer. Bull Exp Biol Med. 2014;157(6):781–784.
Chen L, Madura K. Increased proteasome activity, ubiquitin-conjugating enzymes, and eEF1A translation factor detected in breast cancer tissue. Cancer Res. 2005;65(13):5599–606.
Article CAS PubMed Google Scholar
Munakata K, Uemura M, Tanaka S, et al. Cancer stem-like properties in colorectal cancer cells with low proteasome activity. Clin Cancer Res. 2016;22(21):5277–86.
Article CAS PubMed Google Scholar
Pan J, Zhang Q, Wang Y, You M. 26S proteasome activity is down-regulated in lung cancer stem-like cells propagated in vitro. PLoS One. 2010;5(10):e13298.
Article PubMed PubMed Central Google Scholar
Meusser B, Hirsch C, Jarosch E, Sommer T. ERAD: the long road to destruction. Nat Cell Biol. 2005;7(8):766–72.
Article CAS PubMed Google Scholar
Bernasconi R, Molinari M. ERAD and ERAD tuning: disposal of cargo and of ERAD regulators from the mammalian ER. Curr Opin Cell Biol. 2011;23(2):176–83.
Article CAS PubMed Google Scholar
Yamanaka K, Sasagawa Y, Ogura T. Recent advances in p97/VCP/Cdc48 cellular functions. Biochim Biophys Acta. 2012;1823(1):130–7.
Article CAS PubMed Google Scholar
Merksamer PI, Papa FR. The UPR and cell fate at a glance. J Cell Sci. 2010;123(Pt 7):1003–6.
Article CAS PubMed PubMed Central Google Scholar
Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell. 2000;5(5):897–904.
Fels DR, Koumenis C. The PERK/eIF2alpha/ATF4 module of the UPR in hypoxia resistance and tumor growth. Cancer Biol Ther. 2006;5(7):723–8.
Article CAS PubMed Google Scholar
Novoa I, Zeng H, Harding HP, Ron D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol. 2001;153(5):1011–22.
Article CAS PubMed PubMed Central Google Scholar
Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001;107(7):881–91.
Article CAS PubMed Google Scholar
Maurel M, Chevet E, Tavernier J, Gerlo S. Getting RIDD of RNA: IRE1 in cell fate regulation. Trends Biochem Sci. 2014;39(5):245–54.
Article CAS PubMed Google Scholar
Okada T, Haze K, Nadanaka S, et al. A serine protease inhibitor prevents endoplasmic reticulum stress-induced cleavage but not transport of the membrane-bound transcription factor ATF6. J Biol Chem. 2003;278(33):31024–32.
Article CAS PubMed Google Scholar
Ye J, Rawson RB, Komuro R, et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell. 2000;6(6):1355–64.
Article CAS PubMed Google Scholar
Wang Y, Shen J, Arenzana N, Tirasophon W, Kaufman RJ, Prywes R. Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response. J Biol Chem. 2000;275(35):27013–20.
Article CAS PubMed Google Scholar
Adachi Y, Yamamoto K, Okada T, Yoshida H, Harada A, Mori K. ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum. Cell Struct Funct. 2008;33(1):75–89.
Article CAS PubMed Google Scholar
Yamamoto K, Sato T, Matsui T, et al. Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. Dev Cell. 2007;13(3):365–76.
Article CAS PubMed Google Scholar
Oshi M, Roy AM, Gandhi S, et al. The clinical relevance of unfolded protein response signaling in breast cancer. Am J Cancer Res. 2022;12(6):2627–40.
CAS PubMed PubMed Central Google Scholar
Robinson CM, Talty A, Logue SE, Mnich K, Gorman AM, Samali A. An emerging role for the unfolded protein response in pancreatic cancer. Cancers (Basel). 2021;13(2):261.
Article CAS PubMed Google Scholar
Su S, Shi YT, Chu Y, et al. Section 62 promotes gastric cancer metastasis through mediating UPR-induced autophagy activation. Cell Mol Life Sci. 2022;79(2):133.
Article CAS PubMed PubMed Central Google Scholar
Shen X, Xue Y, Si Y, et al. The unfolded protein response potentiates epithelial-to-mesenchymal transition (EMT) of gastric cancer cells under severe hypoxic conditions. Med Oncol. 2015;32(1):447.
Article PubMed Google Scholar
Patel A, Oshi M, Yan L, Matsuyama R, Endo I, Takabe K. The unfolded protein response is associated with cancer proliferation and worse survival in hepatocellular carcinoma. Cancers (Basel). 2021;13(17):4443.
Article CAS PubMed Google Scholar
Liu J, Xiao M, Li J, et al. Activation of UPR signaling pathway is associated with the malignant progression and poor prognosis in prostate cancer. Prostate. 2017;77(3):274–81.
Article CAS PubMed Google Scholar
Obacz J, Avril T, Le Reste PJ, et al. Endoplasmic reticulum proteostasis in glioblastoma-from molecular mechanisms to therapeutic perspectives. Sci Signal. 2017;10(470):eaal2323.
Article PubMed Google Scholar
Vandewynckel YP, Laukens D, Bogaerts E, et al. Modulation of the unfolded protein response impedes tumor cell adaptation to proteotoxic stress: a PERK for hepatocellular carcinoma therapy. Hepatol Int. 2014;9(1):93–104.
Article PubMed Google Scholar
Costa-Mattioli M, Walter P. The integrated stress response: from mechanism to disease. Science. 2020;368(6489):eaat5314.
Article CAS PubMed PubMed Central Google Scholar
Hurwitz B, Guzzi N, Gola A, et al. The integrated stress response remodels the microtubule-organizing center to clear unfolded proteins following proteotoxic stress. Elife. 2022;11:e77780.
Article CAS PubMed PubMed Central Google Scholar
Bauer B, Martens S, Ferrari L. Aggrephagy at a glance. J Cell Sci. 2023;136(10):jcs260888.
Article CAS PubMed Google Scholar
De Leonibus C, Maddaluno M, Ferriero R, et al. Sestrin2 drives ER-phagy in response to protein misfolding. Dev Cell. 2024;59(16):2035-2052.e10.
Article PubMed PubMed Central Google Scholar
Rudinskiy M, Molinari M. ER-to-lysosome-associated degradation in a nutshell: mammalian, yeast, and plant ER-phagy as induced by misfolded proteins. FEBS Lett. 2023;597(15):1928–45.
Article CAS PubMed Google Scholar
Solvik TA, Nguyen TA, Tony Lin YH, et al. Secretory autophagy maintains proteostasis upon lysosome inhibition. J Cell Biol. 2022;221(6).
Rzymski T, Milani M, Pike L, et al. Regulation of autophagy by ATF4 in response to severe hypoxia. Oncogene. 2010;29(31):4424–35.
Article CAS PubMed Google Scholar
Rouschop KM, van den Beucken T, Dubois L, et al. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Invest. 2010;120(1):127–41.
Article CAS PubMed Google Scholar
B’chir W, Maurin AC, Carraro V, et al. The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. 2013;41(16):7683–99.
Article PubMed PubMed Central Google Scholar
Dey S, Tameire F, Koumenis C. PERK-ing up autophagy during MYC-induced tumorigenesis. Autophagy. 2013;9(4):612–4.
Article CAS PubMed PubMed Central Google Scholar
Hart LS, Cunningham JT, Datta T, et al. Er stress-mediated autophagy promotes Myc-dependent transformation and tumor growth. J Clin Invest. 2012;122(12):4621–34.
Article CAS PubMed PubMed Central Google Scholar
Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood. 2006;107(12):4907–16.
Article CAS PubMed PubMed Central Google Scholar
Menéndez-Benito V, Verhoef LG, Masucci MG, Dantuma NP. Endoplasmic reticulum stress compromises the ubiquitin-proteasome system. Hum Mol Genet. 2005;14(19):2787–99.
Article PubMed Google Scholar
Bao W, Gu Y, Ta L, Wang K, Xu Z. Induction of autophagy by the MG–132 proteasome inhibitor is associated with endoplasmic reticulum stress in MCF–7 cells. Mol Med Rep. 2016;13(1):796–804.
Article CAS PubMed Google Scholar
Kocaturk NM, Gozuacik D. Crosstalk between mammalian autophagy and the ubiquitin-proteasome system. Front Cell Dev Biol. 2018;6:128.
Article PubMed PubMed Central Google Scholar
Brancolini C, Iuliano L. Proteotoxic stress and cell death in cancer cells. Cancers (Basel). 2020;12(9):2385.
Article CAS PubMed Google Scholar
Glab JA, Doerflinger M, Nedeva C, et al. DR5 and caspase-8 are dispensable in ER stress-induced apoptosis. Cell Death Differ. 2017;24(5):944–50.
Article CAS PubMed PubMed Central Google Scholar
Liu X, Yue P, Chen S, et al. The proteasome inhibitor PS-341 (bortezomib) up-regulates DR5 expression leading to induction of apoptosis and enhancement of TRAIL-induced apoptosis despite up-regulation of c-FLIP and survivin expression in human NSCLC cells. Cancer Res. 2007;67(10):4981–8.
Article CAS PubMed Google Scholar
Law ME, Dulloo ZM, Eggleston SR, et al. DR5 disulfide bonding functions as a sensor and effector of protein folding stress. Mol Cancer Res. Published online March 19, 2024. doi:10.1158/1541-7786.
Lam M, Marsters SA, Ashkenazi A, Walter P. Misfolded proteins bind and activate death receptor 5 to trigger apoptosis during unresolved endoplasmic reticulum stress. Elife. 2020;9:e52291.
Article CAS PubMed PubMed Central Google Scholar
Zappa F, Muniozguren NL, Conrad JE, Acosta-Alvear D. The integrated stress response engages a cell-autonomous, ligand-independent, DR5-driven apoptosis switch. Cell Death Dis. 2025;16(1):101.
Article CAS PubMed PubMed Central Google Scholar
Puthalakath H, O’Reilly LA, Gunn P, et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell. 2007;129(7):1337–1349.
Sopha P, Ren HY, Grove DE, Cyr DM. Endoplasmic reticulum stress-induced degradation of DNAJB12 stimulates BOK accumulation and primes cancer cells for apoptosis. J Biol Chem. 2017;292(28):11792–803.
Article CAS PubMed PubMed Central Google Scholar
Zinatizadeh MR, Schock B, Chalbatani GM, Zarandi PK, Jalali SA, Miri SR. The nuclear factor kappa B (NF-kB) signaling in cancer development and immune diseases. Genes Dis. 2020;8(3):287–97.
Article PubMed PubMed Central Google Scholar
Roccaro AM, Sacco A, Aujay M, et al. Selective inhibition of chymotrypsin-like activity of the immunoproteasome and constitutive proteasome in Waldenstrom macroglobulinemia. Blood. 2010;115(20):4051–60.
Article CAS PubMed PubMed Central Google Scholar
Delic J, Masdehors P, Omura S, et al. The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-alpha-initiated apoptosis. Br J Cancer. 1998;77(7):1103–1107.
Domingo-Domènech J, Pippa R, Tápia M, Gascón P, Bachs O, Bosch M. Inactivation of NF-kappaB by proteasome inhibition contributes to increased apoptosis induced by histone deacetylase inhibitors in human breast cancer cells. Breast Cancer Res Treat. 2008;112(1):53–62.
Article PubMed Google Scholar
Hideshima T, Ikeda H, Chauhan D, et al. Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells. Blood. 2009;114(5):1046–1052.
Singha B, Gatla HR, Manna S, et al. Proteasome inhibition increases recruitment of IκB kinase β (IKKβ), S536P-p65, and transcription factor EGR1 to interleukin-8 (IL-8) promoter, resulting in increased IL-8 production in ovarian cancer cells. J Biol Chem. 2014;289(5):2687–700.
Article CAS PubMed Google Scholar
Yu GY, Wang X, Zheng SS, et al. RA190, a proteasome subunit ADRM1 inhibitor, suppresses intrahepatic cholangiocarcinoma by inducing NF-KB-mediated cell apoptosis. Cell Physiol Biochem. 2018;47(3):1152–66.
Article CAS PubMed Google Scholar
Zhu X, Huang L, Gong J, et al. NF-κB pathway link with ER stress-induced autophagy and apoptosis in cervical tumor cells. Cell Death Discov. 2017;3:17059.
Article CAS PubMed PubMed Central Google Scholar
Fan P, Tyagi AK, Agboke FA, Mathur R, Pokharel N, Jordan VC. Modulation of nuclear factor-kappa B activation by the endoplasmic reticulum stress sensor PERK to mediate estrogen-induced apoptosis in breast cancer cells. Cell Death Discov. 2018;4:15.
Article PubMed PubMed Central Google Scholar
Liu M, Fan Y, Li D, et al. Ferroptosis inducer erastin sensitizes NSCLC cells to celastrol through activation of the ROS-mitochondrial fission-mitophagy axis. Mol Oncol. 2021;15(8):2084–105.
Article CAS PubMed PubMed Central Google Scholar
Jia G, Wu W, Chen L, et al. HSF1 is a novel prognostic biomarker in high-risk prostate cancer that correlates with ferroptosis. Discover Oncol. 2023;14(1):107.
Article CAS Google Scholar
Chen X, Li J, Kang R, Klionsky DJ, Tang D. Ferroptosis: machinery and regulation. Autophagy. 2021;17(9):2054–81.
Article CAS PubMed Google Scholar
Yang J, Xu H, Wu W, et al. Ferroptosis signaling promotes the release of misfolded proteins via exosomes to rescue ER stress in hepatocellular carcinoma. Free Radic Biol Med. 2023;202:110–20.
Article CAS PubMed Google Scholar
Li J, Cao F, Yin HL, et al. Ferroptosis: past, present and future. Cell Death Dis. 2020;11(2):88.
Article PubMed PubMed Central Google Scholar
Ullman E, Fan Y, Stawowczyk M, Chen HM, Yue Z, Zong WX. Autophagy promotes necrosis in apoptosis-deficient cells in response to ER stress. Cell Death Differ. 2008;15(2):422–5.
Article CAS PubMed Google Scholar
Moriwaki K, Chan FK. Regulation of RIPK3- and RHIM-dependent necroptosis by the proteasome. J Biol Chem. 2016;291(11):5948–59.
Article CAS PubMed PubMed Central Google Scholar
Ali M, Mocarski ES. Proteasome inhibition blocks necroptosis by attenuating death complex aggregation. Cell Death Dis. 2018;9(3):346.
Article PubMed PubMed Central Google Scholar
Newton K, Wickliffe KE, Dugger DL, et al. Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis. Nature. 2019;574(7778):428–31.
Article CAS PubMed Google Scholar
Tian RD, Chen YQ, He YH, et al. Phosphorylation of eIF2α mitigates endoplasmic reticulum stress and hepatocyte necroptosis in acute liver injury. Ann Hepatol. 2020;19(1):79–87.
Article CAS PubMed Google Scholar
Ma YM, Peng YM, Zhu QH, et al. Novel CHOP activator LGH00168 induces necroptosis in A549 human lung cancer cells via ROS-mediated ER stress and NF-κB inhibition. Acta Pharmacol Sin. 2016;37(10):1381–90.
Article CAS PubMed PubMed Central Google Scholar
Krętowski R, Stypułkowska A, Cechowska-Pasko M. Efficient apoptosis and necrosis induction by proteasome inhibitor: bortezomib in the DLD-1 human colon cancer cell line. Mol Cell Biochem. 2015;398(1–2):165–73.
Article PubMed Google Scholar
Fels DR, Ye J, Segan AT, et al. Preferential cytotoxicity of bortezomib toward hypoxic tumor cells via overactivation of endoplasmic reticulum stress pathways. Cancer Res. 2008;68(22):9323–30.
Article CAS PubMed PubMed Central Google Scholar
Xu CC, Lin YF, Huang MY, et al. Paraptosis: a non-classical paradigm of cell death for cancer therapy. Acta Pharmacol Sin. 2024;45(2):223–37.
Article CAS PubMed Google Scholar
Lyu WY, Cao J, Deng WQ, et al. Xerophenone H, a naturally-derived proteasome inhibitor, triggers apoptosis and paraptosis in lung cancer. Phytomedicine. 2025;141:156647.
Article CAS PubMed Google Scholar
Seo MJ, Kim IY, Lee DM, et al. Dual inhibition of thioredoxin reductase and proteasome is required for auranofin-induced paraptosis in breast cancer cells. Cell Death Dis. 2023;14(1):42.
Article CAS PubMed PubMed Central Google Scholar
Yoon MJ, Kang YJ, Lee JA, et al. Stronger proteasomal inhibition and higher CHOP induction are responsible for more effective induction of paraptosis by dimethoxycurcumin than curcumin. Cell Death Dis. 2014;5(3):e1112.
Article CAS PubMed PubMed Central Google Scholar
Lee HJ, Lee DM, Seo MJ, Kang HC, Kwon SK, Choi KS. PSMD14 targeting triggers paraptosis in breast cancer cells by inducing proteasome inhibition and Ca2 + imbalance. Int J Mol Sci. 2022;23(5):2648.
Article CAS PubMed PubMed Central Google Scholar
Lee AR, Seo MJ, Kim J, et al. Lercanidipine synergistically enhances bortezomib cytotoxicity in cancer cells via enhanced endoplasmic reticulum stress and mitochondrial Ca2 + overload. Int J Mol Sci. 2019;20(24):6112.
Article CAS PubMed PubMed Central Google Scholar
Lee DM, Seo MJ, Lee HJ, Jin HJ, Choi KS. Isrib plus bortezomib triggers paraptosis in breast cancer cells via enhanced translation and subsequent proteotoxic stress. Biochem Biophys Res Commun. 2022;596:56–62.
Article CAS PubMed Google Scholar
Zhang C, Xu H, Tang Q, et al. CaMKII suppresses proteotoxicity by phosphorylating BAG3 in response to proteasomal dysfunction. EMBO Rep. 2024;25(10):4488–514.
Article CAS PubMed PubMed Central Google Scholar
Tsvetkov P, Coy S, Petrova B, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022;375(6586):1254–61.
Article CAS PubMed PubMed Central Google Scholar
Zhang C, Huang T, Li L. Targeting cuproptosis for cancer therapy: mechanistic insights and clinical perspectives. J Hematol Oncol. 2024;17(1):68.
Article PubMed PubMed Central Google Scholar
Tsvetkov P, Detappe A, Cai K, et al. Mitochondrial metabolism promotes adaptation to proteotoxic stress. Nat Chem Biol. 2019;15(7):681–9.
Article CAS PubMed PubMed Central Google Scholar
Tundo GR, Sbardella D, Santoro AM, et al. The proteasome as a druggable target with multiple therapeutic potentialities: cutting and non-cutting edges. Pharmacol Ther. 2020;213:107579.
Article CAS PubMed PubMed Central Google Scholar
Field-Smith A, Morgan GJ, Davies FE. Bortezomib (Velcadetrade mark) in the treatment of multiple myeloma. Ther Clin Risk Manag. 2006;2(3):271–9.
Article CAS PubMed PubMed Central Google Scholar
Chen X, Wu X, Li L, Zhu X. Development of Proteasome Inhibitors for Cancer Therapy. Int J Drug Discov Pharm. 2024; 100004–100004.
Roth P, Gorlia T, Reijneveld JC, et al. Marizomib for patients with newly diagnosed glioblastoma: a randomized phase 3 trial. Neuro Oncol. 2024;26(9):1670–82.
Article CAS PubMed PubMed Central Google Scholar
Liu SJ, Raleigh DR, de Groot JF. Proteasome inhibition for glioblastoma: lessons learned and new opportunities. Neuro Oncol. 2024;26(9):1683–4.
Article CAS PubMed PubMed Central Google Scholar
Yang H, Chen D, Cui QC, Yuan X, Dou QP. Celastrol, a triterpene extracted from the Chinese thunder of God vine, is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. Cancer Res. 2006;66(9):4758–65.
Article CAS PubMed Google Scholar
Zhong YL, Xu GJ, Huang S, et al. Celastrol induce apoptosis of human multiple myeloma cells involving inhibition of proteasome activity. Eur J Pharmacol. 2019;853:184–92.
Article CAS PubMed Google Scholar
Kraus M, Bader J, Geurink PP, et al. The novel β2-selective proteasome inhibitor LU-102 synergizes with bortezomib and carfilzomib to overcome proteasome inhibitor resistance of myeloma cells. Haematologica. 2015;100(10):1350–60.
Article CAS PubMed PubMed Central Google Scholar
Kazi A, Lawrence H, Guida WC, et al. Discovery of a novel proteasome inhibitor selective for cancer cells over non-transformed cells. Cell Cycle. 2009;8(12):1940–51.
Article CAS PubMed Google Scholar
Wang X, D’Arcy P, Caulfield TR, et al. Synthesis and evaluation of derivatives of the proteasome deubiquitinase inhibitor b-AP15. Chem Biol Drug Des. 2015;86(5):1036–1048.
Kapuria V, Peterson LF, Fang D, Bornmann WG, Talpaz M, Donato NJ. Deubiquitinase inhibition by small-molecule WP1130 triggers aggresome formation and tumor cell apoptosis. Cancer Res. 2010;70(22):9265–76.
Article CAS PubMed Google Scholar
Li J, Yakushi T, Parlati F, et al. Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11. Nat Chem Biol. 2017;13(5):486–93.
Article CAS PubMed PubMed Central Google Scholar
Barghout SH, Patel PS, Wang X, et al. Preclinical evaluation of the selective small-molecule UBA1 inhibitor, TAK-243, in acute myeloid leukemia. Leukemia. 2019;33(1):37–51.
Article CAS PubMed Google Scholar
Majeed S, Aparnathi MK, Nixon KCJ, et al. Targeting the ubiquitin-proteasome system using the UBA1 inhibitor TAK-243 is a potential therapeutic strategy for small-cell lung cancer. Clin Cancer Res. 2022;28(9):1966–78.
Article CAS PubMed PubMed Central Google Scholar
Yang Y, Kitagaki J, Dai RM, et al. Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics. Cancer Res. 2007;67(19):9472–81.
Article CAS PubMed Google Scholar
Dikshit A, Jin YJ, Degan S, et al. UBE2N promotes melanoma growth via MEK/FRA1/SOX10 signaling. Cancer Res. 2018;78(22):6462–72.
Article CAS PubMed PubMed Central Google Scholar
Ahmad I. Transition metal complexes as proteasome inhibitors for cancer treatment. Inorganica Chimica Acta. 2020;506.
Chen D, Cui QC, Yang H, et al. Clioquinol, a therapeutic agent for Alzheimer’s disease, has proteasome-inhibitory, androgen receptor-suppressing, apoptosis-inducing, and antitumor activities in human prostate cancer cells and xenografts. Cancer Res. 2007;67(4):1636–44.
Article CAS PubMed Google Scholar
Momose I, Watanabe T. Tyropeptins, proteasome inhibitors produced by Kitasatospora sp. MK993-dF2. J Antibiot (Tokyo). 2017;70(5):542–50.
Article CAS PubMed Google Scholar
Zang M, Li Z, Liu L, et al. Anti-tumor activity of the proteasome inhibitor BSc2118 against human multiple myeloma. Cancer Lett. 2015;366(2):173–81.
Article CAS PubMed Google Scholar
Li Z, Nie J, Zhou R, et al. Thiostrepton suppresses colorectal cancer progression through reactive oxygen species related endoplasmic reticulum stress. Toxicol Appl Pharmacol. 2025;495:117221.
Article CAS PubMed Google Scholar
Jenkins TW, Fitzgerald JE, Park J, et al. Highly specific immunoproteasome inhibitor M3258 induces proteotoxic stress and apoptosis in KMT2A::AFF1 driven acute lymphoblastic leukemia. Sci Rep. 2025;15(1):17284.
Article CAS PubMed PubMed Central Google Scholar
Kuhn DJ, Hunsucker SA, Chen Q, Voorhees PM, Orlowski M, Orlowski RZ. Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors. Blood. 2009;113(19):4667–76.
Article CAS PubMed PubMed Central Google Scholar
Coughlin K, Anchoori R, Iizuka Y, et al. Small-molecule RA-9 inhibits proteasome-associated DUBs and ovarian cancer in vitro and in vivo via exacerbating unfolded protein responses. Clin Cancer Res. 2014;20(12):3174–86.
Article CAS PubMed PubMed Central Google Scholar
Cersosimo U, Sgorbissa A, Foti C, et al. Synthesis, characterization, and optimization for in vivo delivery of a nonselective isopeptidase inhibitor as new antineoplastic agent. J Med Chem. 2015;58(4):1691–704.
Article CAS PubMed Google Scholar
Iuliano L, Dalla E, Picco R, et al. Proteotoxic stress-induced apoptosis in cancer cells: understanding the susceptibility and enhancing the potency. Cell Death Discov. 2022;8(1):407.
Article CAS PubMed PubMed Central Google Scholar
Losada A, Berlanga JJ, Molina-Guijarro JM, et al. Generation of endoplasmic reticulum stress and inhibition of autophagy by plitidepsin induces proteotoxic apoptosis in cancer cells. Biochem Pharmacol. 2020;172.
Phillips E, van Enk S, Kildgaard S, et al. Malformin c preferentially kills glioblastoma stem-like cells via concerted induction of proteotoxic stress and autophagic flux blockade. Mol Oncol. 2025;19(3):785–807.
Article CAS PubMed Google Scholar
Raymundo DP, Doultsinos D, Guillory X, Carlesso A, Eriksson LA, Chevet E. Pharmacological targeting of IRE1 in cancer. Trends Cancer. 2020;6(12):1018–30.
Article CAS PubMed Google Scholar
Yu M, Lun J, Zhang H, et al. Targeting UPR branches, a potential strategy for enhancing efficacy of cancer chemotherapy. Acta Biochim Biophys Sin. 2021;53(11):1417–27.
Article CAS PubMed Google Scholar
Marciniak SJ, Chambers JE, Ron D. Pharmacological targeting of endoplasmic reticulum stress in disease. Nat Rev Drug Discov. 2022;21(2):115–40.
Article CAS PubMed Google Scholar
Alasiri G, Jiramongkol Y, Zona S, et al. Regulation of PERK expression by FOXO3: a vulnerability of drug-resistant cancer cells. Oncogene. 2019;38(36):6382–98.
Article CAS PubMed PubMed Central Google Scholar
Yu ZZ, Xu BQ, Wang YY, Zhang PW, Shu YB, Shi Z. GSK2606414 sensitizes ABCG2-overexpressing multidrug-resistant colorectal cancer cells to chemotherapeutic drugs. Biomedicines. 2023;11(11):3103.
Article CAS PubMed PubMed Central Google Scholar
Cai W, Sun X, Jin F, et al. PERK-eIF2α-ERK1/2 axis drives mesenchymal-endothelial transition of cancer-associated fibroblasts in pancreatic cancer. Cancer Lett. 2021;515:86–95.
Article CAS PubMed Google Scholar
Axten JM, Romeril SP, Shu A, et al. Discovery of GSK2656157: an optimized PERK inhibitor selected for preclinical development. ACS Med Chem Lett. 2013;4(10):964–8.
Article CAS PubMed PubMed Central Google Scholar
Rojas-Rivera D, Delvaeye T, Roelandt R, et al. When PERK inhibitors turn out to be new potent RIPK1 inhibitors: critical issues on the specificity and use of GSK2606414 and GSK2656157. Cell Death Differ. 2017;24(6):1100–10.
Article CAS PubMed PubMed Central Google Scholar
Smith AL, Andrews KL, Beckmann H, et al. Discovery of 1H-pyrazol-3(2h)-ones as potent and selective inhibitors of protein kinase R-like endoplasmic reticulum kinase (PERK). J Med Chem. 2015;58(3):1426–41.
Article CAS PubMed Google Scholar
Mohamed E, Sierra RA, Trillo-Tinoco J, et al. The Unfolded Protein Response Mediator PERK Governs Myeloid Cell-Driven Immunosuppression in Tumors through Inhibition of STING Signaling. Immunity. 2020;52(4):668–682.e7.
Calvo V, Surguladze D, Li AH, et al. Discovery of 2-amino-3-amido-5-aryl-pyridines as highly potent, orally bioavailable, and efficacious PERK kinase inhibitors. Bioorg Med Chem Lett. 2021;43:128058.
Article CAS PubMed Google Scholar
Stokes ME, Calvo V, Fujisawa S, et al. PERK inhibition by HC-5404 sensitizes renal cell carcinoma tumor models to antiangiogenic tyrosine kinase inhibitors. Clin Cancer Res. 2023;29(23):4870–82.
Article CAS PubMed PubMed Central Google Scholar
Gallagher CM, Garri C, Cain EL, et al. Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch. Elife. 2016;5:e11878.
Article PubMed PubMed Central Google Scholar
Torres SE, Gallagher CM, Plate L, et al. Ceapins block the unfolded protein response sensor ATF6α by inducing a neomorphic inter-organelle tether. Elife. 2019;8:e46595.
Article PubMed PubMed Central Google Scholar
Gallagher CM, Walter P. Ceapins inhibit ATF6α signaling by selectively preventing transport of ATF6α to the Golgi apparatus during ER stress. Elife. 2016;5:e11880.
Article PubMed PubMed Central Google Scholar
Zhao R, Lv Y, Feng T, et al. ATF6α promotes prostate cancer progression by enhancing PLA2G4A-mediated arachidonic acid metabolism and protecting tumor cells against ferroptosis. Prostate. 2022;82(5):617–29.
Article CAS PubMed PubMed Central Google Scholar
Zhou H, Zhang T, Chen L, et al. The functional implication of ATF6α in castration-resistant prostate cancer cells. FASEB J. 2023;37(2):e22758.
Article CAS PubMed Google Scholar
Ding WX, Ni HM, Gao W, et al. Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol. 2007;171(2):513–24.
Article CAS PubMed PubMed Central Google Scholar
Albornoz N, Bustamante H, Soza A, Burgos P. Cellular responses to proteasome inhibition: molecular mechanisms and beyond. Int J Mol Sci. 2019;20(14):3379.
Article CAS PubMed PubMed Central Google Scholar
Lytton J, Westlin M, Hanley MR. Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps. J Biol Chem. 1991;266(26):17067–71.
Article CAS PubMed Google Scholar
Johnson AJ, Hsu AL, Lin HP, Song X, Chen CS. The cyclo-oxygenase-2 inhibitor celecoxib perturbs intracellular calcium by inhibiting endoplasmic reticulum Ca2+-ATPases: a plausible link with its anti-tumour effect and cardiovascular risks. Biochem J. 2002;366(Pt 3):831–7.
Article CAS PubMed PubMed Central Google Scholar
Görlach A, Klappa P, Kietzmann T. The endoplasmic reticulum: folding, calcium homeostasis, signaling, and redox control. Antioxid Redox Signal. 2006;8(9–10):1391–418.
Article PubMed Google Scholar
Wu J, Chen S, Liu H, et al. Tunicamycin specifically aggravates ER stress and overcomes chemoresistance in multidrug-resistant gastric cancer cells by inhibiting N-glycosylation. J Exp Clin Cancer Res. 2018;37(1):272.
Article CAS PubMed PubMed Central Google Scholar
Wang Y, Zhang L, He Z, et al. Tunicamycin induces ER stress and inhibits tumorigenesis of head and neck cancer cells by inhibiting N-glycosylation. Am J Transl Res. 2020;12(2):541–50.
CAS PubMed PubMed Central Google Scholar
Wang J, Chen M, Wang M, et al. The novel ER stress inducer Sec C triggers apoptosis by sulfating ER cysteine residues and degrading YAP via ER stress in pancreatic cancer cells [published correction appears in Acta Pharm Sin B. 2025;15(2):1208–1209. doi: 10.1016/j.apsb.2024.10.013.]. Acta Pharm Sin B. 2022;12(1):210–227.
Axten JM, Medina JR, Feng Y, et al. Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J Med Chem. 2012;55(16):7193–207.
Article CAS PubMed Google Scholar
Doan NT, Paulsen ES, Sehgal P, et al. Targeting thapsigargin towards tumors. Steroids. 2015;97:2–7.
Article CAS PubMed Google Scholar
Wen B, Wei YT, Mu LL, Wen GR, Zhao K. The molecular mechanisms of celecoxib in tumor development. Medicine (Baltimore). 2020;99(40):e22544.
Article CAS PubMed Google Scholar
Wang Q, Shinkre BA, Lee JG, et al. The ERAD inhibitor Eeyarestatin I is a bifunctional compound with a membrane-binding domain and a p97/VCP inhibitory group. PLoS One. 2010;5(11):e15479.
Article PubMed PubMed Central Google Scholar
Lee DM, Kim IY, Lee HJ, et al. Akt enhances the vulnerability of cancer cells to VCP/p97 inhibition-mediated paraptosis. Cell Death Dis. 2024;15(1):48.
Article CAS PubMed PubMed Central Google Scholar
Magnaghi P, D’Alessio R, Valsasina B, et al. Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death. Nat Chem Biol. 2013;9(9):548–556.
Zhao Z, Wu M, Zhang X, et al. CB-5083, an inhibitor of P97, suppresses osteosarcoma growth and stem cell properties by altering protein homeostasis. Am J Transl Res. 2020;12(6):2956–2967.
Anderson DJ, Le Moigne R, Djakovic S, et al. Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis. Cancer Cell. 2015;28(5):653–65.
Article CAS PubMed PubMed Central Google Scholar
Her NG, Kesari S, Nurmemmedov E. Thrombospondin-1 counteracts the p97 inhibitor CB-5083 in colon carcinoma cells. Cell Cycle. 2020;19(13):1590–601.
Article CAS PubMed PubMed Central Google Scholar
Kilgas S, Ramadan K. Inhibitors of the ATPase p97/VCP: from basic research to clinical applications. Cell Chem Biol. 2023;30(1):3–21.
Article CAS PubMed Google Scholar
Roux B, Vaganay C, Vargas JD, et al. Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor. Sci Transl Med. 2021;13(587):eabg1168.
Article CAS PubMed PubMed Central Google Scholar
Chou TF, Brown SJ, Minond D, et al. Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways. Proc Natl Acad Sci U S A. 2011;108(12):4834–9.
Article CAS PubMed PubMed Central Google Scholar
Redding A, Grabocka E. Stress granules and hormetic adaptation of cancer. Trends Cancer. 2023;9(12):995–1005.
Article CAS PubMed PubMed Central Google Scholar
Protter DSW, Parker R. Principles and properties of stress granules. Trends Cell Biol. 2016;26(9):668–79.
Article CAS PubMed PubMed Central Google Scholar
Yoon YJ, Kim JA, Shin KD, et al. KRIBB11 inhibits HSP70 synthesis through inhibition of heat shock factor 1 function by impairing the recruitment of positive transcription elongation factor b to the hsp70 promoter. J Biol Chem. 2011;286(3):1737–47.
Article CAS PubMed Google Scholar
Ohnishi K, Takahashi A, Yokota S, Ohnishi T. Effects of a heat shock protein inhibitor KNK437 on heat sensitivity and heat tolerance in human squamous cell carcinoma cell lines differing in p53 status. Int J Radiat Biol. 2004;80(8):607–14.
Article CAS PubMed Google Scholar
Massey AJ, Williamson DS, Browne H, et al. A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother Pharmacol. 2010;66(3):535–45.
Article CAS PubMed Google Scholar
Wen W, Liu W, Shao Y, Chen L. VER-155008, a small molecule inhibitor of HSP70 with potent anti-cancer activity on lung cancer cell lines. Exp Biol Med (Maywood). 2014;239(5):638–45.
Article PubMed Google Scholar
Dong J, Wu Z, Wang D, et al. Hsp70 binds to the androgen receptor N-terminal domain and modulates the receptor function in prostate cancer cells. Mol Cancer Ther. 2019;18(1):39–50.
Article CAS PubMed Google Scholar
Xu F, Lin D, Jiang W, et al. HSP70 inhibitor VER155008 suppresses pheochromocytoma cell and xenograft growth by inhibition of PI3K/AKT/mTOR and MEK/ERK pathways. Int J Clin Exp Pathol. 2019;12(7):2585–94.
CAS PubMed PubMed Central Google Scholar
Fewell SW, Smith CM, Lyon MA, et al. Small molecule modulators of endogenous and co-chaperone-stimulated Hsp70 ATPase activity. J Biol Chem. 2004;279(49):51131–40.
Article CAS PubMed Google Scholar
Gamerdinger M, Kaya AM, Wolfrum U, Clement AM, Behl C. BAG3 mediates chaperone-based aggresome-targeting and selective autophagy of misfolded proteins. EMBO Rep. 2011;12(2):149–56.
Article CAS PubMed PubMed Central Google Scholar
Li X, Colvin T, Rauch JN, et al. Validation of the Hsp70-Bag3 protein-protein interaction as a potential therapeutic target in cancer. Mol Cancer Ther. 2015;14(3):642–8.
Article CAS PubMed PubMed Central Google Scholar
Schopf FH, Biebl MM, Buchner J. The HSP90 chaperone machinery. Nat Rev Mol Cell Biol. 2017;18(6):345–60.
Article CAS PubMed Google Scholar
Fukuyo Y, Hunt CR, Horikoshi N. Geldanamycin and its anti-cancer activities. Cancer Lett. 2010;290(1):24–35.
Article CAS PubMed Google Scholar
Dimopoulos MA, Mitsiades CS, Anderson KC, Richardson PG. Tanespimycin as antitumor therapy. Clin Lymphoma Myeloma Leuk. 2011;11(1):17–22.
Article CAS PubMed Google Scholar
Alzebari AM, Qadir AM, Rafaat MS, Salihi A. Therapeutic potential of heat shock protein 90 inhibitors, geldanamycin, and analog compounds in precision cancer therapy. BioMed Target Journal. 2023;1(2):2–21.
Article Google Scholar
Li ZN, Luo Y. HSP90 inhibitors and cancer: prospects for use in targeted therapies (review). Oncol Rep. 2023;49(1):6.
Article PubMed Google Scholar
Eccles SA, Massey A, Raynaud FI, et al. NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Res. 2008;68(8):2850–60.
Article CAS PubMed Google Scholar
Donnelly A, Blagg BS. Novobiocin and additional inhibitors of the Hsp90 C-terminal nucleotide-binding pocket. Curr Med Chem. 2008;15(26):2702–17.
Article CAS PubMed PubMed Central Google Scholar
Allan RK, Mok D, Ward BK, Ratajczak T. Modulation of chaperone function and cochaperone interaction by novobiocin in the C-terminal domain of Hsp90: evidence that coumarin antibiotics disrupt Hsp90 dimerization. J Biol Chem. 2006;281(11):7161–71.
Article CAS PubMed Google Scholar
Dai J, Zhu M, Qi X, et al. Fungal mycotoxin penisuloxazin A, a novel C-terminal Hsp90 inhibitor and characteristics of its analogues on Hsp90 function related to binding sites. Biochem Pharmacol. 2020;182:114218.
Article CAS PubMed Google Scholar
Li GH, Miao Y, Chen H, et al. The small-molecule drug homoharringtonine targets HSF1 to suppress pancreatic cancer progression. Am J Cancer Res. 2024;14(5):2072–87.
Article CAS PubMed PubMed Central Google Scholar
Qi W, White MC, Choi W, et al. Inhibition of inducible heat shock protein-70 (hsp72) enhances bortezomib-induced cell death in human bladder cancer cells. PLoS One. 2013;8(7):e69509.
Article CAS PubMed PubMed Central Google Scholar
Neznanov N, Gorbachev AV, Neznanova L, et al. Anti-malaria drug blocks proteotoxic stress response: anti-cancer implications. Cell Cycle. 2009;8(23):3960–70.
Article CAS PubMed Google Scholar
Pan X, Mao TY, Mai YW, et al. Discovery of quinacrine as a potent Topo II and Hsp90 dual-target inhibitor, repurposing for cancer therapy. Molecules. 2022;27(17):5561.
Article CAS PubMed PubMed Central Google Scholar
Li N, Wang T, Li Z, et al. Dorsomorphin induces cancer cell apoptosis and sensitizes cancer cells to HSP90 and proteasome inhibitors by reducing nuclear heat shock factor 1 levels. Cancer Biol Med. 2019;16(2):220–233.
Santagata S, Mendillo ML, Tang YC, et al. Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state. Science. 2013;341(6143):1238303.
Article PubMed PubMed Central Google Scholar
Zhang L, Fok JJ, Mirabella F, et al. Hsp70 inhibition induces myeloma cell death via the intracellular accumulation of immunoglobulin and the generation of proteotoxic stress. Cancer Lett. 2013;339(1):49–59.
Article CAS PubMed PubMed Central Google Scholar
Adam C, Baeurle A, Brodsky JL, et al. The HSP70 modulator MAL3-101 inhibits Merkel cell carcinoma. PLoS One. 2014;9(4):e92041.
Article PubMed PubMed Central Google Scholar
Yaglom JA, Wang Y, Li A, et al. Cancer cell responses to Hsp70 inhibitor JG-98: comparison with Hsp90 inhibitors and finding synergistic drug combinations. Sci Rep. 2018;8(1):3010.
Article PubMed PubMed Central Google Scholar
Sydor JR, Normant E, Pien CS, et al. Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90. Proc Natl Acad Sci U S A. 2006;103(46):17408–13.
Article CAS PubMed PubMed Central Google Scholar
Patterson J, Palombella VJ, Fritz C, Normant E. IPI-504, a novel and soluble HSP-90 inhibitor, blocks the unfolded protein response in multiple myeloma cells. Cancer Chemother Pharmacol. 2008;61(6):923–32.
Article CAS PubMed Google Scholar
Lundgren K, Zhang H, Brekken J, et al. BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90. Mol Cancer Ther. 2009;8(4):921–9.
Article CAS PubMed Google Scholar
Zhang J, Liu L, Li Y, et al. HSP90 C-terminal domain inhibition promotes VDAC1 oligomerization via decreasing K274 mono-ubiquitination in Hepatocellular Carcinoma. Neoplasia. 2023;44:100935.
Chen H, Gong Y, Ma Y, et al. A brain-penetrating Hsp90 inhibitor NXD30001 inhibits glioblastoma as a monotherapy or in combination with radiation. Front Pharmacol. 2020;11:974.
Article CAS PubMed PubMed Central Google Scholar
Hassan AMIA, Zhao Y, Chen X, He C. Blockage of autophagy for cancer therapy: a comprehensive review. Int J Mol Sci. 2024;25(13):7459.
Article CAS PubMed PubMed Central Google Scholar
Sedlacek J. Impact of proteostasis workload on sensitivity to proteasome inhibitors in multiple myeloma. Clin Exp Med. 2025;25(1):176.
Article PubMed PubMed Central Google Scholar
Mimnaugh EG, Xu W, Vos M, Yuan X, Neckers L. Endoplasmic reticulum vacuolization and valosin-containing protein relocalization result from simultaneous hsp90 inhibition by geldanamycin and proteasome inhibition by velcade. Mol Cancer Res. 2006;4(9):667–81.
Article CAS PubMed Google Scholar
Peron M, Bonvini P, Rosolen A. Effect of inhibition of the ubiquitin-proteasome system and Hsp90 on growth and survival of rhabdomyosarcoma cells in vitro. BMC Cancer. 2012;12:233.
Article CAS PubMed PubMed Central Google Scholar
Hui B, Shi YH, Ding ZB, et al. Proteasome inhibitor interacts synergistically with autophagy inhibitor to suppress proliferation and induce apoptosis in hepatocellular carcinoma. Cancer. 2012;118(22):5560–71.
Article CAS PubMed Google Scholar
Vogl DT, Stadtmauer EA, Tan KS, et al. Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma. Autophagy. 2014;10(8):1380–90.
Article CAS PubMed PubMed Central Google Scholar
Van dewynckel YP, Coucke C, Laukens D, et al. Next-generation proteasome inhibitor oprozomib synergizes with modulators of the unfolded protein response to suppress hepatocellular carcinoma. Oncotarget. 2016;7(23):34988–5000.
Article Google Scholar
Creedican S, Robinson CM, Mnich K, et al. Inhibition of IRE1α RNase activity sensitizes patient-derived acute myeloid leukaemia cells to proteasome inhibitors. J Cell Mol Med. 2022;26(16):4629–33.
Article CAS PubMed PubMed Central Google Scholar
Chen L, Li Q, She T, et al. IRE1α-XBP1 signaling pathway, a potential therapeutic target in multiple myeloma. Leuk Res. 2016;49:7–12.
Article CAS PubMed Google Scholar
Milan E, Perini T, Resnati M, et al. A plastic SQSTM1/p62-dependent autophagic reserve maintains proteostasis and determines proteasome inhibitor susceptibility in multiple myeloma cells. Autophagy. 2015;11(7):1161–78.
Article CAS PubMed PubMed Central Google Scholar
Zhu K, Dunner K Jr., McConkey DJ. Proteasome inhibitors activate autophagy as a cytoprotective response in human prostate cancer cells. Oncogene. 2010;29(3):451–62.
Article CAS PubMed Google Scholar
Wu WK, Wu YC, Yu L, Li ZJ, Sung JJ, Cho CH. Induction of autophagy by proteasome inhibitor is associated with proliferative arrest in colon cancer cells. Biochem Biophys Res Commun. 2008;374(2):258–63.
Article CAS PubMed Google Scholar
Lou Z, Ren T, Peng X, et al. Bortezomib induces apoptosis and autophagy in osteosarcoma cells through mitogen-activated protein kinase pathway in vitro. J Int Med Res. 2013;41(5):1505–19.
Article CAS PubMed Google Scholar
Sha Z, Schnell HM, Ruoff K, Goldberg A. Rapid induction of p62 and GABARAPL1 upon proteasome inhibition promotes survival before autophagy activation. J Cell Biol. 2018;217(5):1757–76.
Article CAS PubMed PubMed Central Google Scholar
Zhang C, Huang C, Xia H, Xu H, Tang Q, Bi F. Autophagic sequestration of SQSTM1 disrupts the aggresome formation of ubiquitinated proteins during proteasome inhibition. Cell Death Dis. 2022;13(7):615.
Article CAS PubMed PubMed Central Google Scholar
Xiao R, You L, Zhang L, et al. Inhibiting the IRE1α axis of the unfolded protein response enhances the antitumor effect of AZD1775 in TP53 mutant ovarian cancer. Adv Sci. 2022;9(21):e2105469.
Article Google Scholar
Storniolo A, Alfano V, Carbotta S, Ferretti E, Di Renzo L. IRE1α deficiency promotes tumor cell death and eIF2α degradation through PERK dipendent autophagy. Cell Death Discov. 2018. https://doi.org/10.1038/s41420-017-0002-9.
Article PubMed PubMed Central Google Scholar
Padmanabhan A, Kaushik M, Niranjan R, Richards JS, Ebright B, Venkatasubbu GD. Zinc oxide nanoparticles induce oxidative and proteotoxic stress in ovarian cancer cells and trigger apoptosis independent of p53-mutation status. Appl Surf Sci. 2019;487:807–18.
Article CAS PubMed PubMed Central Google Scholar
Snyder CM, Rohde MM, Fahrenholtz CD, et al. Low doses of silver nanoparticles selectively induce lipid peroxidation and proteotoxic stress in mesenchymal subtypes of triple-negative breast cancer. Cancers (Basel). 2021;13(16):4217.
Article CAS PubMed Google Scholar
Wang J, Huang M, Chen S, et al. Nanomedicine-mediated ubiquitination inhibition boosts antitumor immune response via activation of dendritic cells. Nano Res. 2021;14:3900–6.
Article CAS Google Scholar
Dutta D, Liu J, Wen K, et al. BCMA-targeted bortezomib nanotherapy improves therapeutic efficacy, overcomes resistance, and modulates the immune microenvironment in multiple myeloma. Blood Cancer J. 2023;13(1):184.
Article PubMed PubMed Central Google Scholar
Nigro A, Frattaruolo L, Fava M, et al. Bortezomib-loaded mesoporous silica nanoparticles selectively alter metabolism and induce death in multiple myeloma cells. Cancers (Basel). 2020;12(9):2709.
Article CAS PubMed Google Scholar
Wang M, Cai X, Yang J, et al. A targeted and ph-responsive bortezomib nanomedicine in the treatment of metastatic bone tumors. ACS Appl Mater Interfaces. 2018;10(48):41003–11.
Article CAS PubMed Google Scholar
Chui MH, Doodnauth SA, Erdmann N, et al. Chromosomal instability and mTORC1 activation through PTEN loss contribute to proteotoxic stress in ovarian carcinoma. Cancer Res. 2019;79(21):5536–49.
Article PubMed Google Scholar
Glaviano A, Foo ASC, Lam HY, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 2023;22(1):138.
Article CAS PubMed PubMed Central Google Scholar
Lee YJ, Seol A, Lee M, et al. A phase II trial to evaluate the efficacy of Bortezomib and Liposomal Doxorubicin in patients with BRCA wild-type platinum-resistant recurrent ovarian cancer (KGOG 3044/EBLIN). In Vivo. 2022;36(4):1949–58.
Article CAS PubMed PubMed Central Google Scholar
Jiang TY, Pan YF, Wan ZH, et al. PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma. Sci Transl Med. 2020;12(562):eaay0152.
Article CAS PubMed Google Scholar
Jiang TY, Feng XF, Fang Z, et al. Pten deficiency facilitates the therapeutic vulnerability to proteasome inhibitor bortezomib in gallbladder cancer. Cancer Lett. 2021;501:187–99.
Article CAS PubMed Google Scholar
Benitez JA, Finlay D, Castanza A, et al. PTEN deficiency leads to proteasome addiction: a novel vulnerability in glioblastoma. Neuro Oncol. 2021;23(7):1072–86.
Article CAS PubMed PubMed Central Google Scholar
Wang M, Ferreira RB, Law ME, et al. A novel proteotoxic combination therapy for EGFR + and HER2 + cancers. Oncogene. 2019;38(22):4264–82.
Article CAS PubMed Google Scholar
Singh N, Joshi R, Komurov K. HER2-mTOR signaling-driven breast cancer cells require ER-associated degradation to survive. Sci Signal. 2015;8(378):ra52.
Article PubMed Google Scholar
Riggelen J, Yetil A, Felsher DW. MYC as a regulator of ribosome biogenesis and protein synthesis. Nat Rev Cancer. 2010;10(4):301–9.
Article PubMed Google Scholar
Zhao N, Cao J, Xu L, et al. Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer. J Clin Invest. 2018;128(4):1283–99.
Article PubMed PubMed Central Google Scholar
Frenzel A, Zirath H, Vita M, Albihn A, Henriksson MA. Identification of cytotoxic drugs that selectively target tumor cells with MYC overexpression. PLoS One. 2011;6(11):e27988.
Article CAS PubMed PubMed Central Google Scholar
Tameire F, Verginadis II, Leli NM, et al. Atf4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression. Nat Cell Biol. 2019;21(7):889–99.
Article CAS PubMed PubMed Central Google Scholar
Suzuki T, Kishikawa T, Sato T, et al. Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells. Cancer Gene Ther. 2022;29(5):505–18.
Article CAS PubMed Google Scholar
Drilon A, Schoenfeld AJ, Arbour KC, et al. Exceptional responders with invasive mucinous adenocarcinomas: a phase 2 trial of bortezomib in patients with KRAS G12D-mutant lung cancers. Cold Spring Harb Mol Case Stud. 2019;5(2):a003665.
Article CAS PubMed PubMed Central Google Scholar
Ren S, Smith MJ, Louro ID, et al. The p44S10 locus, encoding a subunit of the proteasome regulatory particle, is amplified during progression of cutaneous malignant melanoma. Oncogene. 2000;19(11):1419–27.
Article CAS PubMed Google Scholar
Vriend J, Klonisch T. Genes of the ubiquitin proteasome system qualify as differential markers in malignant glioma of astrocytic and oligodendroglial origin. Cell Mol Neurobiol. 2023;43(4):1425–52.
Article CAS PubMed Google Scholar
Busse A, Kraus M, Na IK, et al. Sensitivity of tumor cells to proteasome inhibitors is associated with expression levels and composition of proteasome subunits. Cancer. 2008;112(3):659–70.
Article CAS PubMed Google Scholar
Sajadimajd S, Khazaei M. Oxidative stress and cancer: the role of Nrf2. Curr Cancer Drug Targets. 2018;18(6):538–57.
Article CAS PubMed Google Scholar
Shirazi F, Jones RJ, Singh RK, et al. Activating KRAS, NRAS, and BRAF mutants enhance proteasome capacity and reduce endoplasmic reticulum stress in multiple myeloma. Proc Natl Acad Sci U S A. 2020;117(33):20004–14.
Article CAS PubMed PubMed Central Google Scholar
Sung K, Hosoya K, Deguchi T, et al. Glutathione-associated redox regulation alleviates radio-resistance of canine cancer stem-like cells with low proteasome activity. Sci Rep. 2025;15(1):18017.
Article CAS PubMed PubMed Central Google Scholar
Li D, Yallowitz A, Ozog L, Marchenko N. A gain-of-function mutant p53-HSF1 feed forward circuit governs adaptation of cancer cells to proteotoxic stress. Cell Death Dis. 2014;5(4):e1194.
Article CAS PubMed PubMed Central Google Scholar
Chougoni KK, Neely V, Ding B, et al. Oncogenic mutant p53 sensitizes non-small cell lung cancer cells to proteasome inhibition via oxidative stress-dependent induction of mitochondrial apoptosis. Cancer Res Commun. 2024;4(10):2685–98.
Article CAS PubMed PubMed Central Google Scholar
Walerych D, Lisek K, Sommaggio R, et al. Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer. Nat Cell Biol. 2016;18(8):897–909.
Article CAS PubMed Google Scholar
Vogiatzi F, Brandt DT, Schneikert J, et al. Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5. Proc Natl Acad Sci U S A. 2016;113(52):E8433–42.
Article CAS PubMed PubMed Central Google Scholar
Isermann T, Şener ÖÇ, Stender A, et al. Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity. Nat Commun. 2021;12(1):4019.
Article CAS PubMed PubMed Central Google Scholar
Isermann T, Schneider KL, Wegwitz F, et al. Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition. Cell Death Differ. Published online April 9, 2025. https://doi.org/10.1038/s41418-025-01502-x.
Manni S, Brancalion A, Mandato E, et al. Protein kinase CK2 inhibition down modulates the NF-κB and STAT3 survival pathways, enhances the cellular proteotoxic stress and synergistically boosts the cytotoxic effect of bortezomib on multiple myeloma and mantle cell lymphoma cells. PLoS One. 2013;8(9):e75280.
Article CAS PubMed PubMed Central Google Scholar
Tomihara H, Carbone F, Perelli L, et al. Loss of ARID1A promotes epithelial-mesenchymal transition and sensitizes pancreatic tumors to proteotoxic stress. Cancer Res. 2021;81(2):332–43.
Article PubMed Google Scholar
Murai Y, Jo U, Murai J, et al. SLFN11 inactivation induces proteotoxic stress and sensitizes cancer cells to ubiquitin activating enzyme inhibitor TAK-243. Cancer Res. 2021;81(11):3067–78.
Article CAS PubMed PubMed Central Google Scholar
Moreno R, Banerjee S, Jackson AW, et al. The stress-responsive kinase DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress. Cell Death Differ. 2021;28(5):1563–78.
Article CAS PubMed Google Scholar
Parzych K, Saavedra-García P, Valbuena GN, et al. The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation. Oncogene. 2019;38(17):3216–31.
Article CAS PubMed PubMed Central Google Scholar
Adamczyk-Grochala J, Bloniarz D, Zielinska K, Lewinska A, Wnuk M. DNMT2/TRDMT1 gene knockout compromises doxorubicin-induced unfolded protein response and sensitizes cancer cells to ER stress-induced apoptosis. Apoptosis. 2023;28(1–2):166–85.
Article CAS PubMed Google Scholar
Zeidan Q, Tian JL, Ma J, Eslami F, Hart GW. O-GlcNAcylation of ribosome-associated proteins is concomitant with translational reprogramming during proteotoxic stress. J Biol Chem. 2024;300(11):107877.
Article CAS PubMed PubMed Central Google Scholar
Marino S, Petrusca DN, Bishop RT, et al. Pharmacologic targeting of the p62 ZZ domain enhances both anti-tumor and bone-anabolic effects of bortezomib in multiple myeloma. Haematologica. 2024;109(5):1501–1513.
Ö. Ö, Örd D, Kaikkonen MU, Örd T. Pharmacological or TRIB3-mediated suppression of ATF4 transcriptional activity promotes hepatoma cell resistance to proteasome inhibitor bortezomib. Cancers (Basel). 2021;13(10):2341.
Article Google Scholar
Li C, Xia J, Franqui-Machin R, et al. TRIP13 modulates protein deubiquitination and accelerates tumor development and progression of B cell malignancies. J Clin Invest. 2021;131(14):e146893.
Article CAS PubMed PubMed Central Google Scholar
Zhang C, Duan Y, Huang C, Li L. Inhibition of SQSTM1 S403 phosphorylation facilitates the aggresome formation of ubiquitinated proteins during proteasome dysfunction. Cell Mol Biol Lett. 2023;28(1):85.
Article CAS PubMed PubMed Central Google Scholar
Zhang C, Gao J, Li M, Deng Y, Jiang C. P38δ MAPK regulates aggresome biogenesis by phosphorylating SQSTM1 in response to proteasomal stress. J Cell Sci. 2018;131(14):jcs216671.
Article PubMed Google Scholar
Babagana M, Brown LR, Slabodkin HZ, Kichina JV, Kandel ES. Proteotoxic stress as an exploitable vulnerability in cells with hyperactive AKT. Int J Mol Sci. 2021;22(21):11376.
Article CAS PubMed PubMed Central Google Scholar
Leung-Hagesteijn C, Erdmann N, Cheung G, et al. Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma. Cancer Cell. 2013;24(3):289–304.
Article CAS PubMed PubMed Central Google Scholar
Chauhan D, Li G, Shringarpure R, et al. Blockade of Hsp27 overcomes Bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res. 2003;63(19):6174–7.
CAS PubMed Google Scholar
Gu C, Wang Y, Zhang L, et al. AHSA1 is a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma. J Exp Clin Cancer Res. 2022;41(1):11.
Article CAS PubMed PubMed Central Google Scholar
Zhang X, Lin C, Song J, et al. Parkin facilitates proteasome inhibitor-induced apoptosis via suppression of NF-κB activity in hepatocellular carcinoma. Cell Death Dis. 2019;10(10):719.
Article CAS PubMed PubMed Central Google Scholar
Kim HJ, Kim HJ, Kim SY, Roh J, Yun JH, Kim CH. TBK1 is a signaling hub in coordinating stress-adaptive mechanisms in head and neck cancer progression. Autophagy. 2025. https://doi.org/10.1080/15548627.2025.2481661.
Article PubMed PubMed Central Google Scholar
Rapino F, Jung M, Fulda S. BAG3 induction is required to mitigate proteotoxicity via selective autophagy following inhibition of constitutive protein degradation pathways. Oncogene. 2014;33(13):1713–24.
Article CAS PubMed Google Scholar
Zhang C, Tang Q, Xia H, Xu H, Bi F. PKM2 compensates for proteasome dysfunction by mediating the formation of the CHIP-HSP70-BAG3 complex and the aggregation of ubiquitinated proteins. FASEB J. 2022;36(1):e22121.
Article CAS PubMed Google Scholar
Xie J, Van Damme P, Fang D, Proud CG. Ablation of elongation factor 2 kinase enhances heat-shock protein 90 chaperone expression and protects cells under proteotoxic stress. J Biol Chem. 2019;294(18):7169–76.
Article CAS PubMed Google Scholar
Mateos MV, Prosper F, Martin Sánchez J, et al. Phase I study of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Cancer Med. 2023;12(4):3999–4009.
Article CAS PubMed Google Scholar
Kunder R, Velyunskiy M, Dunne SF, et al. Synergistic PIM kinase and proteasome inhibition as a therapeutic strategy for MYC-overexpressing triple-negative breast cancer. Cell Chem Biol. 2022;29(3):358-372.e5.
Article CAS PubMed Google Scholar
Lee SW, Yeon SK, Kim GW, et al. Hdac6-selective inhibitor overcomes bortezomib resistance in multiple myeloma. Int J Mol Sci. 2021;22(3):1341.
Article CAS PubMed PubMed Central Google Scholar
Huang H, Liu N, Yang C, et al. HDAC inhibitor L-carnitine and proteasome inhibitor bortezomib synergistically exert anti-tumor activity in vitro and in vivo. PLoS One. 2012;7(12):e52576.
Article CAS PubMed PubMed Central Google Scholar
Suárez-Martínez E, Piersma SR, Pham TV, Bijnsdorp IV, Jimenez CR, Carnero A. Protein homeostasis maintained by HOOK1 levels promotes the tumorigenic and stemness properties of ovarian cancer cells through reticulum stress and autophagy. J Exp Clin Cancer Res. 2024;43(1):150.
Article CAS PubMed PubMed Central Google Scholar
Chen L, Yang X. TRIM11 cooperates with HSF1 to suppress the anti-tumor effect of proteotoxic stress drugs. Cell Cycle. 2019;18(1):60–8.
Article CAS PubMed Google Scholar
Gong C, Krupka JA, Gao J, et al. Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis. Mol Cell. 2021;81(19):4059–4075.e11.
Chroma K, Mistrik M, Moudry P, et al. Tumors overexpressing RNF168 show altered DNA repair and responses to genotoxic treatments, genomic instability and resistance to proteotoxic stress. Oncogene. 2017;36(17):2405–22.
Article CAS PubMed Google Scholar
Avril T, Vauléon E, Chevet E. Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers. Oncogenesis. 2017;6(8):e373.
Article CAS PubMed PubMed Central Google Scholar
Hasan A, Rizvi SF, Parveen S, Mir SS. Molecular chaperones in DNA repair mechanisms: role in genomic instability and proteostasis in cancer. Life Sci. 2022;306:120852.
Article CAS PubMed Google Scholar
Madden E, Logue SE, Healy SJ, Manie S, Samali A. The role of the unfolded protein response in cancer progression: from oncogenesis to chemoresistance. Biol Cell. 2019;111(1):1–17.
Article PubMed Google Scholar
Chern YJ, Tai IT. Adaptive response of resistant cancer cells to chemotherapy. Cancer Biol Med. 2020;17(4):842–63.
Article CAS PubMed PubMed Central Google Scholar
Bahar E, Kim JY, Yoon H. Chemotherapy resistance explained through endoplasmic reticulum stress-dependent signaling. Cancers (Basel). 2019;11(3):338.
Article CAS PubMed Google Scholar
Ghai S, Shrestha R, Su KH. HSF1 at the crossroads of chemoresistance: from current insights to future horizons in cell death mechanisms. Front Cell Dev Biol. 2025;12:1500880.
Article PubMed PubMed Central Google Scholar
Gumilar KE, Chin Y, Ibrahim IH, et al. Heat shock factor 1 inhibition: a novel anti-cancer strategy with promise for precision oncology. Cancers (Basel). 2023;15(21):5167.
Article CAS PubMed Google Scholar
Krawczyk Z, Gogler-Pigłowska A, Sojka DR, Scieglinska D. The role of heat shock proteins in Cisplatin resistance. Anticancer Agents Med Chem. 2018;18(15):2093–109.
Article CAS PubMed Google Scholar
Yun CW, Kim HJ, Lim JH, Lee SH. Heat shock proteins: agents of cancer development and therapeutic targets in anti-cancer therapy. Cells. 2019;9(1):60.
Article PubMed PubMed Central Google Scholar
Chin KV, Tanaka S, Darlington G, Pastan I, Gottesman MM. Heat shock and arsenite increase expression of the multidrug resistance (MDR1) gene in human renal carcinoma cells. J Biol Chem. 1990;265(1):221–6.
Article CAS PubMed Google Scholar
Kioka N, Yamano Y, Komano T, Ueda K. Heat-shock responsive elements in the induction of the multidrug resistance gene (MDR1). FEBS Lett. 1992;301(1):37–40.
Article CAS PubMed Google Scholar
Vilaboa NE, Galán A, Troyano A, de Blas E, Aller P. Regulation of multidrug resistance 1 (MDR1)/P-glycoprotein gene expression and activity by heat-shock transcription factor 1 (HSF1). J Biol Chem. 2000;275(32):24970–6.
Article CAS PubMed Google Scholar
Yin L, Yang Y, Zhu W, et al. Heat shock protein 90 triggers multi-drug resistance of ovarian cancer via AKT/GSK3β/β-catenin signaling. Front Oncol. 2021;11:620907.
Article CAS PubMed PubMed Central Google Scholar
Vydra N, Toma A, Glowala-Kosinska M, Gogler-Piglowska A, Widlak W. Overexpression of heat shock transcription factor 1 enhances the resistance of melanoma cells to doxorubicin and paclitaxel. BMC Cancer. 2013;13:504.
Article PubMed PubMed Central Google Scholar
Lombardi R, Sonego M, Pucci B, et al. HSP90 identified by a proteomic approach as druggable target to reverse platinum resistance in ovarian cancer. Mol Oncol. 2021;15(4):1005–23.
Article CAS PubMed PubMed Central Google Scholar
Zhang Z, Xie Z, Sun G, et al. Reversing drug resistance of cisplatin by hsp90 inhibitors in human ovarian cancer cells. Int J Clin Exp Med. 2015;8(5):6687–701.
PubMed PubMed Central Google Scholar
Ewers KM, Patil S, Kopp W, et al. HSP90 inhibition synergizes with cisplatin to eliminate basal-like pancreatic ductal adenocarcinoma cells. Cancers (Basel). 2021;13(24):6163.
Article CAS PubMed Google Scholar
Nagaraju GP, Zakka KM, Landry JC, Shaib WL, Lesinski GB, El-Rayes BF. Inhibition of HSP90 overcomes resistance to chemotherapy and radiotherapy in pancreatic cancer. Int J Cancer. 2019;145(6):1529–37.
Article CAS PubMed Google Scholar
Desai S, Liu Z, Yao J, et al. Heat shock factor 1 (HSF1) controls chemoresistance and autophagy through transcriptional regulation of autophagy-related protein 7 (ATG7). J Biol Chem. 2013;288(13):9165–76.
Article CAS PubMed PubMed Central Google Scholar
Kim YJ, Lee Y, Shin H, Hwang S, Park J, Song EJ. Ubiquitin-proteasome system as a target for anticancer treatment-an update. Arch Pharm Res. 2023;46(7):573–97.
Article CAS PubMed Google Scholar
Paradzik T, Bandini C, Mereu E, et al. The landscape of signaling pathways and proteasome inhibitors combinations in multiple myeloma. Cancers (Basel). 2021;13(6):1235.
Article CAS PubMed Google Scholar
Leonardo-Sousa C, Carvalho AN, Guedes RA, et al. Revisiting proteasome inhibitors: molecular underpinnings of their development, mechanisms of resistance and strategies to overcome anti-cancer drug resistance. Molecules. 2022;27(7):2201.
Article CAS PubMed PubMed Central Google Scholar
Manasanch EE, Orlowski RZ. Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol. 2017;14(7):417–33.
Article CAS PubMed PubMed Central Google Scholar
Gatti L, Zuco V, Zaffaroni N, Perego P. Drug combinations with proteasome inhibitors in antitumor therapy. Curr Pharm Des. 2013;19(22):4094–114.
Article CAS PubMed Google Scholar
Lv X, Lu X, Cao J, et al. Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors. Science. 2023;381(6662):eabn4180.
Article CAS PubMed PubMed Central Google Scholar
Zhou C, Li C, Luo L, et al. Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer. Cancer Cell. 2024;42(7):1286–1300.e8.
Paik A, Purawarga Matada GS, Ghara A, Pal R, Pavani G, Kamurthy H. BRAF inhibitors in melanoma: structural insights, therapeutic resistance, and biological evaluation of quinazoline derivatives. Eur J Med Chem. 2025. https://doi.org/10.1016/j.ejmech.2025.117866.
Article PubMed Google Scholar
Qin Y, Zuo Q, Huang L, Huang L, Merlino G, Yu Y. Perk mediates resistance to BRAF inhibition in melanoma with impaired PTEN. NPJ Precis Oncol. 2021;5(1):68.
Article CAS PubMed PubMed Central Google Scholar
Jandova J, Park SL, Corenblum MJ, et al. Mefloquine induces ER stress and apoptosis in BRAFi-resistant A375-BRAFV600E/NRASQ61K malignant melanoma cells targeting intracranial tumors in a bioluminescent murine model. Mol Carcinog. 2022;61(6):603–14.
Article CAS PubMed PubMed Central Google Scholar
Sanchez JN, Subramanian C, Chanda M, et al. A novel C-terminal Hsp90 inhibitor KU758 synergizes efficacy in combination with BRAF or MEK inhibitors and targets drug-resistant pathways in BRAF-mutant melanomas. Melanoma Res. 2021;31(3):197–207.
Article PubMed PubMed Central Google Scholar
Wu T, Li C, Zhou C, et al. Inhibition of USP14 enhances anti-tumor effect in vemurafenib-resistant melanoma by regulation of Skp2. Cell Biol Toxicol. 2023;39(5):2381–99.
Article CAS PubMed Google Scholar
Wang D, Xu Q, Yuan Q, et al. Proteasome inhibition boosts autophagic degradation of ubiquitinated-AGR2 and enhances the antitumor efficiency of bevacizumab. Oncogene. 2019;38(18):3458–74.
Article CAS PubMed PubMed Central Google Scholar
Yallowitz A, Ghaleb A, Garcia L, Alexandrova EM, Marchenko N. Heat shock factor 1 confers resistance to lapatinib in ERBB2-positive breast cancer cells. Cell Death Dis. 2018;9(6):621.
Article PubMed PubMed Central Google Scholar
Du X, Shao Y, Qin HF, Tai YH, Gao HJ. ALK-rearrangement in non-small-cell lung cancer (NSCLC). Thorac Cancer. 2018;9(4):423–30.
Article CAS PubMed PubMed Central Google Scholar
Tanimoto A, Matsumoto S, Takeuchi S, et al. Proteasome Inhibition Overcomes ALK-TKI Resistance in ALK-Rearranged/TP53-Mutant NSCLC via Noxa Expression. Clin Cancer Res. 2021;27(5):1410–20.
Article CAS PubMed Google Scholar
Huang C, Zhang C, Li J, Duan Y, Tang Q, Bi F. Targeting p38γ synergistically enhances sorafenib-induced cytotoxicity in hepatocellular carcinoma. Cell Biol Toxicol. 2025;41(1):35.
Article CAS PubMed PubMed Central Google Scholar
Prieto-Domínguez N, Ordóñez R, Fernández A, et al. Modulation of Autophagy by Sorafenib: Effects on Treatment Response. Front Pharmacol. 2016;7:151.
Gavini J, Dommann N, Jakob MO, et al. Verteporfin-induced lysosomal compartment dysregulation potentiates the effect of sorafenib in hepatocellular carcinoma. Cell Death Dis. 2019;10(10):749.
Article PubMed PubMed Central Google Scholar
Carpenter RL, Sirkisoon S, Zhu D, et al. Combined inhibition of AKT and HSF1 suppresses breast cancer stem cells and tumor growth. Oncotarget. 2017;8(43):73947–63.
Article PubMed PubMed Central Google Scholar
Ahmed A, Tait SWG. Targeting immunogenic cell death in cancer. Mol Oncol. 2020;14(12):2994–3006.
Mandula JK, Chang S, Mohamed E, et al. Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses. Cancer Cell. 2022;40(10):1145-1160.e9.
Article CAS PubMed PubMed Central Google Scholar
Benvenuto M, Ciuffa S, Focaccetti C, et al. Proteasome inhibition by bortezomib parallels a reduction in head and neck cancer cells growth, and an increase in tumor-infiltrating immune cells. Sci Rep. 2021;11(1):19051.
Maione F, Oddo D, Galvagno F, et al. Preclinical efficacy of carfilzomib in BRAF-mutant colorectal cancer models. Mol Oncol. 2024;18(6):1552–1570.
Batista A, Rodvold JJ, Xian S, et al. IRE1α regulates macrophage polarization, PD-L1 expression, and tumor survival. PLoS Biol. 2020;18(6):e3000687.
Ma J, Tan J, Zhang W, Bai M, Liu K. Prenatal inflammation exposure accelerates lung cancer tumorigenesis in offspring mouse: possible links to IRE1α/XBP1-mediated M2-like polarization of TAMs and PD-L1 up-expression. Cancer Immunol Immunother. 2024;73(5):88.
Zhou Q, Liang J, Yang T, et al. Carfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer. EMBO Mol Med. 2022;14(1):e14502.
Nikotina AD, Vladimirova SA, Kokoreva NE, et al. Novel mechanism of drug resistance triggered by tumor-associated macrophages through Heat Shock Factor-1 activation. Cancer Immunol Immunother. 2024;73(2):25.
Ai L, Chen J, Yan H, et al. Research Status and Outlook of PD-1/PD-L1 Inhibitors for Cancer Therapy. Drug Des Devel Ther. 2020;14:3625–49.
Article CAS PubMed PubMed Central Google Scholar
Zavareh RB, Spangenberg SH, Woods A, Martínez-Peña F, Lairson LL. HSP90 Inhibition Enhances Cancer Immunotherapy by Modulating the Surface Expression of Multiple Immune Checkpoint Proteins. Cell Chem Biol. 2021;28(2):158–168.e5.
Liu K, Huang J, Liu J, et al. HSP90 Mediates IFNγ-Induced Adaptive Resistance to Anti-PD-1 Immunotherapy. Cancer Res. 2022;82(10):2003–2018.
Mehndiratta S, Lin MH, Wu YW, et al. N-alkyl-hydroxybenzoyl anilide hydroxamates as dual inhibitors of HDAC and HSP90, downregulating IFN-γ induced PD-L1 expression [published correction appears in Eur J Med Chem. 2020;199:112406.
Rahmy S, Mishra SJ, Murphy S, Blagg BSJ, Lu X. Hsp90β inhibition upregulates interferon response and enhances immune checkpoint blockade therapy in murine tumors. Front Immunol. 2022;13:1005045.
Article CAS PubMed PubMed Central Google Scholar
Yang T, Ren C, Lu C, et al. Phosphorylation of HSF1 by PIM2 induces PD-L1 expression and promotes tumor growth in breast cancer. Cancer Res. 2019;79(20):5233–44.
Article CAS PubMed Google Scholar
Yuan Y, Jiao P, Wang Z, et al. Endoplasmic reticulum stress promotes the release of exosomal PD-L1 from head and neck cancer cells and facilitates M2 macrophage polarization. Cell Commun Signal. 2022;20(1):12.
Article CAS PubMed PubMed Central Google Scholar
Chou CW, Yang RY, Chan LC, et al. The stabilization of PD-L1 by the endoplasmic reticulum stress protein GRP78 in triple-negative breast cancer. Am J Cancer Res. 2020;10(8):2621–34.
CAS PubMed PubMed Central Google Scholar
Cacan E, Spring AM, Kumari A, Greer SF, Garnett-Benson C. Combination Treatment with Sublethal Ionizing Radiation and the Proteasome Inhibitor, Bortezomib, Enhances Death-Receptor Mediated Apoptosis and Anti-Tumor Immune Attack. Int J Mol Sci. 2015;16(12):30405–21.
Article CAS PubMed PubMed Central Google Scholar
Tamatani T, Takamaru N, Hara K, et al. Bortezomib-enhanced radiosensitization through the suppression of radiation-induced nuclear factor-κB activity in human oral cancer cells. Int J Oncol. 2013;42(3):935–44.
Article CAS PubMed Google Scholar
Kern J, Schilling D, Schneeweis C, et al. Identification of the unfolded protein response pathway as target for radiosensitization in pancreatic cancer. Radiother Oncol. 2024;191:110059.
Kinzel L, Ernst A, Orth M, et al. A novel HSP90 inhibitor with reduced hepatotoxicity synergizes with radiotherapy to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer. Oncotarget. 2016;7(28):43199–219.
Article PubMed PubMed Central Google Scholar
Kim YM, Pyo H. Cooperative enhancement of radiosensitivity after combined treatment of 17-(allylamino)-17-demethoxygeldanamycin and celecoxib in human lung and colon cancer cell lines. DNA Cell Biol. 2012;31(1):15–29.
Noguchi M, Yu D, Hirayama R, et al. Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin. Biochem Biophys Res Commun. 2006;351(3):658–63.
Article CAS PubMed Google Scholar
Dungey FA, Caldecott KW, Chalmers AJ. Enhanced radiosensitization of human glioma cells by combining inhibition of poly(ADP-ribose) polymerase with inhibition of heat shock protein 90. Mol Cancer Ther. 2009;8(8):2243–2254.
Gu C, Zhang J, Gao W, et al. Advances and applications of hyperthermia in tumor therapy: Mechanisms, techniques, and clinical integration. International Communications in Heat and Mass Transfer. 2025; 164:108895.
Chen O, Michlíková S, Eckhardt L, et al. Efficient Heat Shock Response Affects Hyperthermia-Induced Radiosensitization in a Tumor Spheroid Control Probability Assay. Cancers (Basel). 2021;13(13):3168.

Download references

Acknowledgements

Not applicable.

Funding

This work was supported by the National Key Research and Development Program of China (grant number: 2024YFB3311700); Sichuan Science and Technology Program (grant number: 2024YFFK0343).

Author information

Authors and Affiliations

Division of Abdominal Tumor Multimodality Treatment, Cancer Center and Laboratory of Abdominal Tumor Immunology and Microenvironment, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Chenliang Zhang & Dan Cao
Clinical Trial Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Jielang Li
Division of Abdominal Tumor Multimodality Treatment, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Qiulin Tang
Department of Pharmacy, Chengdu Fifth People’s Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
Liping Li
Division of Abdominal Tumor, Department of Medical Oncology/Radiation oncology, Cancer Center, Laboratory of Abdominal Tumor Immunology and Microenvironment, State Key Laboratory of BiotherapyWest China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Dan Cao

Authors

Chenliang Zhang
View author publications
Search author on:PubMed Google Scholar
Jielang Li
View author publications
Search author on:PubMed Google Scholar
Qiulin Tang
View author publications
Search author on:PubMed Google Scholar
Liping Li
View author publications
Search author on:PubMed Google Scholar
Dan Cao
View author publications
Search author on:PubMed Google Scholar

Contributions

D. C. and C. Z. contributed to conception and design of the manuscript; C. Z., J. L., and Q. T. drafted the manuscript and conducted image processing. L. L. contributed to reviewing. D. C. critically reviewed and edited the manuscript; C. Z. given the final approval of the version to be published.

Corresponding authors

Correspondence to Chenliang Zhang or Dan Cao.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Cite this article

Zhang, C., Li, J., Tang, Q. et al. Targeting proteostasis for cancer therapy: current advances, challenges, and future perspectives. Mol Cancer 24, 265 (2025). https://doi.org/10.1186/s12943-025-02472-x

Download citation

Received: 15 July 2025
Accepted: 07 September 2025
Published: 21 October 2025
Version of record: 21 October 2025
DOI: https://doi.org/10.1186/s12943-025-02472-x

Targeting proteostasis for cancer therapy: current advances, challenges, and future perspectives

Abstract

Introduction

Proteostasis network

Proteotoxic stress response in tumor cells

Heat shock response (HSR)

Ubiquitin-proteasome system (UPS)

Unfolded protein response (UPR)

Integrated stress response (ISR)

Autophagy-lysosome pathway (ALP)

Crosstalk between different mechanisms of proteotoxic stress response

Proteotoxicity-induced tumor cell death

Apoptosis

Ferroptosis

Necrosis

Paraptosis

Cuproptosis

Targeting proteostasis for cancer therapy

Targeting UPS

Targeting UPR

Targeting IRE1

Targeting PERK

Targeting ATF6

ER stressors

Targeting ERAD

Targeting ISR

Targeting HSR

Targeting ALP

Challenge of targeting proteostasis for cancer therapy

Targetable vulnerability in proteostasis-targeted tumor therapy

Protein synthesis

Proteasomal activity

Oncogenic mutant p53

Targeting proteostasis to overcome tumor drug resistance

Targeting proteostasis to overcome resistance to tumor chemotherapy

Targeting proteostasis to overcome resistance to tumor-targeted therapy

Targeting proteostasis to enhance tumor immunotherapy

Targeting proteostasis to enhance radiotherapy

Conclusions and future perspectives

Data availability

Abbreviations

References

Acknowledgements

Funding

Author information

Authors and Affiliations

Contributions

Corresponding authors

Ethics declarations

Ethics approval and consent to participate

Consent for publication

Competing interests

Additional information

Publisher’s Note

Rights and permissions

About this article

Cite this article

Share this article

Keywords

Molecular Cancer

Contact us