Introduction

Targeted therapies in cancer treatment have emerged as a promising alternative to conventional methods such as surgery, chemotherapy, and radiation, which are often criticized for their associated toxicity and the potential for disease recurrence1. Imatinib has shown efficacy in treating chronic myelogenous leukemia2, while other targeted therapies have been developed for lung3,4 and breast cancers5,6. Combining targeted therapies with standard treatments has inspired the fight against cancer.

Immunotherapies have also garnered substantial attention in recent years, as they fundamentally transform the cancer treatment landscape and counteract cancer cells by leveraging and activating the immune response against tumors. This process of boosting innate and/or adaptive immune responses through immunomodulation7 is a new powerful therapeutic tool.

Combination therapies, with their potential to reduce the number of drugs needed for tumor regression while launching a multifaceted assault to combat therapeutic resistance and prevent tumor recurrence, present additional therapeutic advantages over monotherapies. More than twenty anticancer combination therapies have received FDA approval, and several clinical trials are currently exploring the therapeutic potential of combination strategies. This promising approach, which offers practical benefits and therapeutic advantages, is a key area of interest in the fight against cancer.

Given its emerging importance, the intercellular transfer of therapeutic resistance warrants deeper investigation in future studies. Although cisplatin-based chemotherapy is commonly employed to treat advanced cancers, the development of resistance remains a significant challenge, with its underlying mechanisms not yet fully elucidated. Emerging evidence suggests that the exosomal transfer of microRNAs (miRNAs) within the tumor microenvironment (TME) plays a crucial role in conferring cisplatin (DDP) resistance. For instance, miR-21 derived from M2-polarized tumor-associated macrophages has been shown to promote DDP resistance in gastric cancer cells by suppressing apoptosis and enhancing PI3K/AKT signaling by downregulating PTEN. Similarly, exosomes derived from cancer-associated fibroblasts (CAFs) can confer cisplatin resistance in NSCLC cells by transferring miR-130a8. The packaging of miR-130a into exosomes is mediated by the RNA-binding protein PUM2, suggesting that CAF-derived exosomal miR-130a may be a potential therapeutic target to overcome cisplatin resistance in NSCLC9. These findings highlight the therapeutic potential of targeting exosome-mediated intercellular communication in the TME to overcome chemotherapy resistance in cancer.

In this Collection, the authors present novel molecules and outline potential mechanisms of action in various preclinical cancer models. Their compelling results could significantly impact and advance our understanding of cancer treatment, potentially leading to transformative changes in clinical settings.

Collection overview

Biegala et al10 demonstrated that reversing BRCA2 mutations enhances therapeutic efficacy of PARP inhibitors (PARPi) in ovarian cancer. The study emphasized the involvement of DNA damage pathways on the therapeutic effects of olaparib, as increased expression of the homologous recombination repair pathway can inhibit its function11,12 by upregulating BRCA1/213. Moreover, inhibiting ATR function—either genetically using siRNA-ATR or pharmacologically with ceralasertib—and inhibiting CHK1 (via MK8776 or siCHK1) significantly improved the efficacy of treatments for ovarian cancer cells harboring BRCA2 mutations.

Targeting epidermal growth factor receptor (EGFR) is considered one of the most effective strategies for treating non-small cell lung cancer (NSCLC), as 10–15% of patients exhibit activation of this pathway 14. Several EGFR tyrosine kinase inhibitors (TKIs), including afatinib and dacomitinib, initially demonstrate promising efficacy; however, resistance often develops over time due to mutations in the catalytic domain of EGFR (T790M)15. Osimertinib, an EGFR mutant TKI, is the first-line treatment choice16. Although patients may show initial responsiveness, many ultimately develop resistance. La Monica et al.17 demonstrated that increased glucosylceramides, downstream effectors of ceramide signaling, may contribute to this resistance. Intratumoral injection of the pharmacological inhibitor 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) sensitized osimertinib-resistant NSCLC models in preclinical studies.

Triple-negative breast cancer (TNBC) occurs in ~ 15–20% of breast cancer patients18, and despite some positive results with PARPi19 or anti-EGFR/TROP2 therapies20,21, virtually all women with TNBC ultimately succumb to metastatic disease22,23,24. To overcome intrinsic resistance, Martin et al.25 identified increased expression of aryl hydrocarbon receptor (AhR) as a negative regulator of STImulator of Interferon Genes (STING) expression26,27, which in turn downregulates IFN-1. The study further demonstrated that PARPi activates AhR signaling, which causes resistance in BRAC1-deficient TNBC cells; hence, combining AhR antagonist (BAY) and PARPi (TAL) synergistically enhances therapeutic efficacy by upregulating IFN-1 production and potentiates PARPi function in BRAC1-negative TNBC cells.

The chemoresistance of TNBC cells to paclitaxel was investigated by Calistri et al28 using single-cell RNA sequencing (scRNA-seq). Their findings revealed that the concurrent induction of innate immune responses by IFNB and IFNG, combined with the downregulation of cell-cycle checkpoint proteins, enables TNBC cells to proliferate. Further studies identified the involvement of three key transcription factors, FOSL1, NFE2L2, and ELF3, which may play critical roles in proliferation and contribute to paclitaxel resistance in TNBC cells. While the role of ELF3 in proliferation, survival, and metastasis is well established in various cancer types29,30, the present study demonstrated that knocking down ELF3 expression caused the cells to arrest at the G1 phase of the cell-cycle and resulted in growth inhibition, thereby enhancing paclitaxel efficacy in TNBC cell lines. Thus, ELF3 expression may predict potential paclitaxel resistance in TNBC cells, and inhibiting ELF3 could amplify the effect of paclitaxel.

Cancer immunotherapy is a new fruitful strategy that boosts the ability of the patient’s immune system to detect and effectively fight cancer cells. Overcoming immune-suppression by targeting single immune checkpoints (PD-1/L1) has already shown clinical benefit, but patients may develop resistance31. Dai and colleagues32 generated a novel bispecific anti-LAG-3-TIGIT antibody (ZGGS15) and found greater antitumor efficacy in mouse models, compared to targeting LAG-3 and TIGIT alone. Interestingly, ZGGS15 in combination with Nivolumab (anti-PD-1) showed synergistic effects for enhanced T-cell responses and thus inhibited tumor growth in mice. Preclinical safety analyses revealed that ZGGS15 does not induce cytokine-release syndrome, which is a serious adverse event of current immunotherapies limiting beneficial therapy responses. Combinatorial immune checkpoint inhibition (ICI) may therefore represent a novel strategy to circumvent immunotherapy resistance. This treatment has sufficiently promising efficacy and warrants further investigation, including in combination with chemotherapy.

The effects of a combination of X-ray or proton irradiation with or without ICI (anti-PD-L1) were investigated in two syngeneic mouse models of head and neck cancer (HNSCC) by Rykkelid et al.33. The authors compared therapeutic efficacy on either well-differentiated (immunogenic) or poorly differentiated (less immunogenic) tumors and found synergistic effects of radiation and ICI in both mouse models for both X-ray and proton radiotherapy. The therapeutic benefit of combined X-ray radiotherapy and ICI was pronounced for well-differentiated tumors, whereas the combination of proton radiotherapy and ICI was superior in poorly differentiated tumors. Since radiation is the backbone of current therapeutic options for HNSCC and many patients develop resistance34, this study illustrated the feasibility of combining radiation with ICI as an effective therapy option.

Tan et al35 revisited an old target and investigated resistance mechanisms to hypomethylating agents (HMAs) in solid tumors. As clinically approved drugs to treat hematological malignancies, HMAs (e.g. azacytidine, decitabine) target DNA methyltransferases to reactivate tumor-suppressor genes and double-stranded RNAs36. As a result, HMAs show antineoplastic activity through promoting cell differentiation, dampening cell proliferation, and inducing apoptosis via viral mimicry. Unfortunately, HMAs have been shown ineffective in solid tumors, and their molecular mechanisms are not fully understood. Strikingly, this study found increased levels of mitochondrial RNA (mtRNA) and higher metabolic activity promoting ATP production in HMA-treated lung cancer cells. As a consequence, interfering with mitochondrial function through downregulating mature mtRNA expression increased cell death. Searching the needle in the haystack, the authors performed CRISPR screening and identified mtRNA-polymerase and ribonuclease ELAC2 as new HMA sensitizers by counteracting mtRNA expression and ATP production. Co-treatment with HMA and IMT-1, a small-molecule inhibitor of mtRNA polymerase, led to reduced mtRNA levels and decreased proliferation compared to single HMA and IMT-1 treatment. This study emphasizes the therapeutic advantage of epigenetic reprogramming and co-targeting mitochondrial regulators in solid cancers.