Abstract
T cell exhaustion is an adaptive and distinct cell fate that emerges in response to persistent antigen stimulation, primarily in chronic infections and cancer. It is characterized by a progressive loss of effector functions and sustained expression of multiple inhibitory receptors. Progression to T cell exhaustion is driven by persistent antigen stimulation through the T cell receptor and is modulated by signals from co-stimulatory and inhibitory molecules as well as by microenvironmental factors such as cytokines, metabolites and neuronal factors. These extrinsic cellular factors reshape the T cell transcriptome, epigenome and metabolism towards a state of exhaustion through critical intrinsic cell regulators. In this Review, we summarize our current understanding of the regulators involved in T cell exhaustion, highlighting their roles in directing the fates and functionalities of distinct exhausted T cell subsets and how they may be harnessed for the development of improved immunotherapies against cancer and chronic infections.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$32.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Wherry, E. J. T cell exhaustion. Nat. Immunol. 12, 492–499 (2011).
McLane, L. M., Abdel-Hakeem, M. S. & Wherry, E. J. CD8 T cell exhaustion during chronic viral infection and cancer. Annu. Rev. Immunol. 37, 457–495 (2019).
Martinez, G. J. et al. The transcription factor NFAT promotes exhaustion of activated CD8+ T cells. Immunity 42, 265–278 (2015).
Liu, X. et al. Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction. Nature 567, 525–529 (2019).
Chen, J. et al. NR4A transcription factors limit CAR T cell function in solid tumours. Nature 567, 530–534 (2019). This study, along with Liu et al. (2019), shows that NR4A transcription factors suppress T cell function and promote their exhaustion in cancer and viral infection.
Scott, A. C. et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571, 270–274 (2019).
Khan, O. et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 571, 211–218 (2019).
Alfei, F. et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 571, 265–269 (2019).
Yao, C. et al. Single-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection. Nat. Immunol. 20, 890–901 (2019). This study, together with Scott et al. (2019), Khan et al. (2019)and Alfei et al. (2019), shows that high levels of TOX expression in T ex cells critically promote T cell exhaustion and support their persistence through transcriptional and epigenetic regulation in chronic viral infection and cancer.
Zebley, C. C., Zehn, D., Gottschalk, S. & Chi, H. T cell dysfunction and therapeutic intervention in cancer. Nat. Immunol. 25, 1344–1354 (2024).
Galluzzi, L., Smith, K. N., Liston, A. & Liston, A. D. The diversity of CD8+ T cell dysfunction in cancer and viral infection. Nat. Rev. Immunol. 25, 662–679 (2025).
Zehn, D., Thimme, R., Lugli, E., de Almeida, G. P. & Oxenius, A. ‘Stem-like’ precursors are the fount to sustain persistent CD8+ T cell responses. Nat. Immunol. 23, 836–847 (2022).
Schietinger, A. et al. Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 45, 389–401 (2016).
Angelosanto, J. M., Blackburn, S. D., Crawford, A. & Wherry, E. J. Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection. J. Virol. 86, 8161–8170 (2012).
McManus, D. T. et al. An early precursor CD8+ T cell that adapts to acute or chronic viral infection. Nature 640, 772–781 (2025).
Chu, T. et al. Precursors of exhausted T cells are pre-emptively formed in acute infection. Nature 640, 782–792 (2025). This study, together with McManus et al. (2025), demonstrates that Tex progenitor cells emerge early during both acute and chronic viral infections and adapt to their antigenic environment by either maintaining a stem-like phenotype under chronic antigen exposure or differentiating into central memory-like T cells in acute infections.
Utzschneider, D. T. et al. T cell factor 1-expressing memory-like CD8+ T cells sustain the immune response to chronic viral infections. Immunity 45, 415–427 (2016). This study, along with Siddiqui et al. (2019) and Im et al. (2016), shows that TCF1 is a key transcription factor essential for Tex progenitor development, maintenance, and the persistence of Tex cells during chronic viral infection and cancer.
Blackburn, S. D., Shin, H., Freeman, G. J. & Wherry, E. J. Selective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade. Proc. Natl Acad. Sci. USA 105, 15016–15021 (2008).
Krishna, S. et al. Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer. Science 370, 1328–1334 (2020).
Siddiqui, I. et al. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50, 195–211.e10 (2019).
Miller, B. C. et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 20, 326–336 (2019). This study, along with Siddiqui et al. (2019), shows that the progenitor subset of intratumoural Tex cells is critical for tumour control and mediates the response to PD1 or PDL1 blockade.
Im, S. J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417–421 (2016).
Hudson, W. H. et al. Proliferating transitory T cells with an effector-like transcriptional signature emerge from PD-1+ stem-like CD8+ T cells during chronic infection. Immunity 51, 1043–1058.e4 (2019). This study, along with Zander et al. (2019), highlights that CX3CR1+ cells represent an effector-like subset of Tex cells and contribute to viral control during chronic viral infection.
Giles, J. R. et al. Shared and distinct biological circuits in effector, memory and exhausted CD8+ T cells revealed by temporal single-cell transcriptomics and epigenetics. Nat. Immunol. 23, 1600–1613 (2022).
Daniel, B. et al. Divergent clonal differentiation trajectories of T cell exhaustion. Nat. Immunol. 23, 1614–1627 (2022).
Zander, R. et al. CD4+ T cell help is required for the formation of a cytolytic CD8+ T cell subset that protects against chronic infection and cancer. Immunity 51, 1028–1042.e4 (2019).
Wang, P. H. et al. Reciprocal transmission of activating and inhibitory signals and cell fate in regenerating T cells. Cell Rep. 42, 113155 (2023).
Prokhnevska, N. et al. CD8+ T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor. Immunity 56, 107–124.e5 (2023).
Schenkel, J. M. et al. Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1+ CD8+ T cells in tumor-draining lymph nodes. Immunity 54, 2338–2353.e6 (2021).
Huang, Q. et al. The primordial differentiation of tumor-specific memory CD8+ T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes. Cell 185, 4049–4066.e25 (2022). This study highlights that the progenitor subset of tumour-specific CD8+ T cells in TDLNs has superior memory potential and a pivotal role in determining the antitumour response and effectiveness of PD1 or PDL1 blockade.
Takahashi, M. et al. Intratumoral antigen signaling traps CD8+ T cells to confine exhaustion to the tumor site. Sci. Immunol. 9, eade2094 (2024).
Bucks, C. M., Norton, J. A., Boesteanu, A. C., Mueller, Y. M. & Katsikis, P. D. Chronic antigen stimulation alone is sufficient to drive CD8+ T cell exhaustion. J. Immunol. 182, 6697–6708 (2009).
Tonnerre, P. et al. Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory. Nat. Immunol. 22, 1030–1041 (2021).
Oliveira, G. et al. Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma. Nature 596, 119–125 (2021).
Wu, J. E. et al. In vitro modeling of CD8+ T cell exhaustion enables CRISPR screening to reveal a role for BHLHE40. Sci. Immunol. 8, eade3369 (2023).
Shakiba, M. et al. TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion. J. Exp. Med. 219, e20201966 (2022).
Snell, L. M. et al. CD8+ T cell priming in established chronic viral infection preferentially directs differentiation of memory-like cells for sustained immunity. Immunity 49, 678–694.e5 (2018).
Burger, M. L. et al. Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes in tumors. Cell 184, 4996–5014.e26 (2021).
Singhaviranon, S., Dempsey, J. P., Hagymasi, A. T., Mandoiu, I. I. & Srivastava, P. K. Low-avidity T cells drive endogenous tumor immunity in mice and humans. Nat. Immunol. 26, 240–251 (2025).
Dahling, S. et al. Type 1 conventional dendritic cells maintain and guide the differentiation of precursors of exhausted T cells in distinct cellular niches. Immunity 55, 656–670.e8 (2022).
Chung, H. K., McDonald, B. & Kaech, S. M. The architectural design of CD8+ T cell responses in acute and chronic infection: parallel structures with divergent fates. J. Exp. Med. 218, e20201730 (2021).
Lan, X. et al. Antitumor progenitor exhausted CD8+ T cells are sustained by TCR engagement. Nat. Immunol. 25, 1046–1058 (2024).
Jansen, C. S. et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature 576, 465–470 (2019).
Meiser, P. et al. A distinct stimulatory cDC1 subpopulation amplifies CD8+ T cell responses in tumors for protective anti-cancer immunity. Cancer Cell 41, 1498–1515.e10 (2023).
Waibl Polania, J. et al. Antigen presentation by tumor-associated macrophages drives T cells from a progenitor exhaustion state to terminal exhaustion. Immunity 58, 232–246.e6 (2025).
Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).
Li, K. et al. PD-1 suppresses TCR-CD8 cooperativity during T-cell antigen recognition. Nat. Commun. 12, 2746 (2021).
Hui, E. et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355, 1428–1433 (2017).
Seo, H. et al. TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion. Proc. Natl Acad. Sci. USA 116, 12410–12415 (2019).
He, C. et al. UFL1 ablation in T cells suppresses PD-1 UFMylation to enhance anti-tumor immunity. Mol. Cell 84, 1120–1138.e8 (2024).
Chamoto, K., Yaguchi, T., Tajima, M. & Honjo, T. Insights from a 30-year journey: function, regulation and therapeutic modulation of PD1. Nat. Rev. Immunol. 23, 682–695 (2023).
Gill, A. L. et al. PD-1 blockade increases the self-renewal of stem-like CD8 T cells to compensate for their accelerated differentiation into effectors. Sci. Immunol. 8, eadg0539 (2023).
Morgan, D. M. et al. Expansion of tumor-reactive CD8+ T cell clonotypes occurs in the spleen in response to immune checkpoint blockade. Sci. Immunol. 9, eadi3487 (2024).
Liu, B. et al. Temporal single-cell tracing reveals clonal revival and expansion of precursor exhausted T cells during anti-PD-1 therapy in lung cancer. Nat. Cancer 3, 108–121 (2022).
Egen, J. G., Kuhns, M. S. & Allison, J. P. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat. Immunol. 3, 611–618 (2002).
Blackburn, S. D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29–37 (2009).
Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007).
Xu, X. et al. CTLA4 depletes T cell endogenous and trogocytosed B7 ligands via cis-endocytosis. J. Exp. Med. 220, e20221391 (2023).
Kennedy, A. et al. Differences in CD80 and CD86 transendocytosis reveal CD86 as a key target for CTLA-4 immune regulation. Nat. Immunol. 23, 1365–1378 (2022).
Agarwal, S. et al. Deletion of the inhibitory co-receptor CTLA-4 enhances and invigorates chimeric antigen receptor T cells. Immunity 56, 2388–2407.e9 (2023). This study shows that deletion of CTLA4 in CAR T cells enhances CD28 co-stimulation, prolongs surface CAR expression and enhances antitumour efficacy.
Seidel, J. A., Otsuka, A. & Kabashima, K. Anti-PD-1 and Anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front. Oncol. 8, 86 (2018).
Wei, S. C. et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 170, 1120–1133.e17 (2017).
Wei, S. C. et al. Negative co-stimulation constrains T cell differentiation by imposing boundaries on possible cell states. Immunity 50, 1084–1098.e10 (2019).
Simpson, T. R. et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210, 1695–1710 (2013).
Burke, K. P., Chaudhri, A., Freeman, G. J. & Sharpe, A. H. The B7:CD28 family and friends: unraveling coinhibitory interactions. Immunity 57, 223–244 (2024).
Joller, N., Anderson, A. C. & Kuchroo, V. K. LAG-3, TIM-3, and TIGIT: distinct functions in immune regulation. Immunity 57, 206–222 (2024).
Freed-Pastor, W. A. et al. The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer. Cancer Cell 39, 1342–1360.e14 (2021).
Wienke, J. et al. Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy. Cancer Cell 42, 283–300.e8 (2024).
Ausejo-Mauleon, I. et al. TIM-3 blockade in diffuse intrinsic pontine glioma models promotes tumor regression and antitumor immune memory. Cancer Cell 41, 1911–1926.e8 (2023).
Dixon, K. O. et al. TIM-3 restrains anti-tumour immunity by regulating inflammasome activation. Nature 595, 101–106 (2021).
Chen, C. et al. Soluble Tim-3 serves as a tumor prognostic marker and therapeutic target for CD8+ T cell exhaustion and anti-PD-1 resistance. Cell Rep. Med. 5, 101686 (2024).
Ma, S. et al. Identification of a small-molecule Tim-3 inhibitor to potentiate T cell-mediated antitumor immunotherapy in preclinical mouse models. Sci. Transl. Med. 15, eadg6752 (2023).
Jiang, Y. et al. Ligand-induced ubiquitination unleashes LAG3 immune checkpoint function by hindering membrane sequestration of signaling motifs. Cell 188, 2354–2371.e18 (2025).
Chikuma, S. et al. PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo. J. Immunol. 182, 6682–6689 (2009).
Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).
Kamphorst, A. O. et al. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 355, 1423–1427 (2017).
Guy, C. et al. LAG3 associates with TCR-CD3 complexes and suppresses signaling by driving co-receptor-Lck dissociation. Nat. Immunol. 23, 757–767 (2022).
Curran, M. A., Montalvo, W., Yagita, H. & Allison, J. P. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl Acad. Sci. USA 107, 4275–4280 (2010).
Wang, K. et al. Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8+ T cells. Cancer Cell 42, 1582–1597.e10 (2024).
Shen, L. et al. First-line cadonilimab plus chemotherapy in HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma: a randomized, double-blind, phase 3 trial. Nat. Med. 31, 1163–1170 (2025).
Gao, X. et al. Cadonilimab with chemotherapy in HER2-negative gastric or gastroesophageal junction adenocarcinoma: the phase 1b/2 COMPASSION-04 trial. Nat. Med. 30, 1943–1951 (2024).
Andrews, L. P. et al. LAG-3 and PD-1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN-γ-dependent anti-tumor immunity. Cell 187, 4355–4372.e22 (2024).
Ngiow, S. F. et al. LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity. Cell 187, 4336–4354.e19 (2024).
Cillo, A. R. et al. Blockade of LAG-3 and PD-1 leads to co-expression of cytotoxic and exhaustion gene modules in CD8+ T cells to promote antitumor immunity. Cell 187, 4373–4388.e15 (2024). This study, together with Andrews et al. (2024) and Ngiow et al. (2024), demonstrates the mechanism underlying the synergistic promotion of CD8+ T cell exhaustion by PD1 and LAG3, and supports their dual blockade as an effective immunotherapeutic strategy to enhance CD8+ T cell responses and improve cancer treatment.
Guo, X. et al. Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer. Cancer Cell 43, 248–268.e9 (2025).
Mathew, D. et al. Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients. Science 384, eadf1329 (2024).
Zak, J. et al. JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma. Science 384, eade8520 (2024).
Humblin, E. et al. Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1+ PD-1+ CD8 T cells. Sci. Immunol. 8, eadg0878 (2023). This study shows that continuous CD28 co-stimulation promotes the persistence of Tex cells during chronic infection, with low-level engagement preserving the self-renewal of Tex cell progenitors, while stronger signalling drives their effector-like differentiation.
Duraiswamy, J. et al. Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation. Cancer Cell 39, 1623–1642.e20 (2021).
Pichler, A. C. et al. TCR-independent CD137 (4-1BB) signaling promotes CD8+-exhausted T cell proliferation and terminal differentiation. Immunity 56, 1631–1648.e10 (2023).
Liu, L. et al. Human/mouse CD137 agonist, JNU-0921, effectively shrinks tumors through enhancing the cytotoxicity of CD8+ T cells in cis and in trans. Sci. Adv. 10, eadp8647 (2024).
Andreata, F. et al. Therapeutic potential of co-signaling receptor modulation in hepatitis B. Cell 187, 4078–4094.e21 (2024).
Jaeger-Ruckstuhl, C. A. et al. Signaling via a CD27-TRAF2-SHP-1 axis during naive T cell activation promotes memory-associated gene regulatory networks. Immunity 57, 287–302.e12 (2024).
Humblin, E. et al. The costimulatory molecule ICOS limits memory-like properties and function of exhausted PD-1+CD8+ T cells. Immunity 58, 1966–1983.e10 (2025).
Stelekati, E. et al. Bystander chronic infection negatively impacts development of CD8+ T cell memory. Immunity 40, 801–813 (2014).
Wu, T. et al. The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. Sci. Immunol. 1, eaai8593 (2016).
Chen, W. et al. Chronic type I interferon signaling promotes lipid-peroxidation-driven terminal CD8+ T cell exhaustion and curtails anti-PD-1 efficacy. Cell Rep. 41, 111647 (2022).
Lukhele, S. et al. The transcription factor IRF2 drives interferon-mediated CD8+ T cell exhaustion to restrict anti-tumor immunity. Immunity 55, 2369–2385.e10 (2022).
Heim, K. et al. Attenuated effector T cells are linked to control of chronic HBV infection. Nat. Immunol. 25, 1650–1662 (2024).
Tinoco, R., Alcalde, V., Yang, Y., Sauer, K. & Zuniga, E. I. Cell-intrinsic transforming growth factor-β signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo. Immunity 31, 145–157 (2009).
Tauriello, D. V. F. et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538–543 (2018).
Saadey, A. A. et al. Rebalancing TGFβ1/BMP signals in exhausted T cells unlocks responsiveness to immune checkpoint blockade therapy. Nat. Immunol. 24, 280–294 (2023).
Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).
Tang, N. et al. TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight 5, e133977 (2020).
Sievers, C. et al. Phenotypic plasticity and reduced tissue retention of exhausted tumor-infiltrating T cells following neoadjuvant immunotherapy in head and neck cancer. Cancer Cell 41, 887–902.e5 (2023).
Chen, W. TGF-β regulation of T cells. Annu. Rev. Immunol. 41, 483–512 (2023).
Sun, Q. et al. BCL6 promotes a stem-like CD8+ T cell program in cancer via antagonizing BLIMP1. Sci. Immunol. 8, eadh1306 (2023). This study shows that the TGFβ–BCL6 axis has a critical role in maintaining Tex cell progenitors in tumours by counteracting the IL-2–BLIMP1 axis, which drives effector-like and terminal differentiation while diminishing stemness.
Gabriel, S. S. et al. Transforming growth factor-β-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection. Immunity 54, 1698–1714.e5 (2021).
Hu, Y. et al. TGF-β regulates the stem-like state of PD-1+ TCF-1+ virus-specific CD8 T cells during chronic infection. J. Exp. Med. 219, e20211574 (2022).
Ma, C. et al. TGF-β promotes stem-like T cells via enforcing their lymphoid tissue retention. J. Exp. Med. 219, e20211538 (2022). This study, along with Gabriel et al. (2021) and Hu et al. (2022), demonstrates that TGFβ signalling is essential for maintaining the stem-like population of Tex cells and promoting their retention in lymphoid tissues during chronic viral infection.
Kalia, V. et al. Prolonged interleukin-2Rα expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo. Immunity 32, 91–103 (2010).
Hashimoto, M. et al. PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program. Nature 610, 173–181 (2022).
Geels, S. N. et al. Interruption of the intratumor CD8+ T cell:Treg crosstalk improves the efficacy of PD-1 immunotherapy. Cancer Cell 42, 1051–1066.e7 (2024).
Liu, Y. et al. IL-2 regulates tumor-reactive CD8+ T cell exhaustion by activating the aryl hydrocarbon receptor. Nat. Immunol. 22, 358–369 (2021).
Wu, W. et al. IL-2Rα-biased agonist enhances antitumor immunity by invigorating tumor-infiltrating CD25+CD8+ T cells. Nat. Cancer 4, 1309–1325 (2023).
West, E. E. et al. PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. J. Clin. Invest. 123, 2604–2615 (2013).
Fröhlich, A. et al. IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science 324, 1576–1580 (2009).
Elsaesser, H., Sauer, K. & Brooks, D. G. IL-21 is required to control chronic viral infection. Science 324, 1569–1572 (2009).
Ren, H. M. et al. IL-21 from high-affinity CD4 T cells drives differentiation of brain-resident CD8 T cells during persistent viral infection. Sci. Immunol. 5, eabb5590 (2020).
Zander, R. et al. Tfh-cell-derived interleukin 21 sustains effector CD8+ T cell responses during chronic viral infection. Immunity 55, 475–493.e5 (2022). This study, together with Zander et al. (2019), shows that IL-21 produced by CD4+ T cells, particularly TFH cells, critically promotes the effector function and differentiation of effector-like Tex cells during chronic viral infection.
Li, Y. et al. Targeting IL-21 to tumor-reactive T cells enhances memory T cell responses and anti-PD-1 antibody therapy. Nat. Commun. 12, 951 (2021).
Cui, W., Liu, Y., Weinstein, J. S., Craft, J. & Kaech, S. M. An interleukin-21-interleukin-10-STAT3 pathway is critical for functional maturation of memory CD8+ T cells. Immunity 35, 792–805 (2011).
Xin, G. et al. A critical role of IL-21-induced BATF in sustaining CD8-T-cell-mediated chronic viral control. Cell Rep. 13, 1118–1124 (2015).
Cui, C. et al. Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses. Cell 184, 6101–6118.e13 (2021). This study highlights that IL-21 produced by TFH cells enhances the effector function and antitumour response of CD8+ T cells.
Brooks, D. G. et al. IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection. Proc. Natl Acad. Sci. USA 105, 20428–20433 (2008).
Brooks, D. G. et al. Interleukin-10 determines viral clearance or persistence in vivo. Nat. Med. 12, 1301–1309 (2006).
Ejrnaes, M. et al. Resolution of a chronic viral infection after interleukin-10 receptor blockade. J. Exp. Med. 203, 2461–2472 (2006).
Laidlaw, B. J. et al. Production of IL-10 by CD4+ regulatory T cells during the resolution of infection promotes the maturation of memory CD8+ T cells. Nat. Immunol. 16, 871–879 (2015).
Smith, L. K. et al. Interleukin-10 directly inhibits CD8+ T cell function by enhancing N-glycan branching to decrease antigen sensitivity. Immunity 48, 299–312.e5 (2018).
Macatonia, S. E., Doherty, T. M., Knight, S. C. & O’Garra, A. Differential effect of IL-10 on dendritic cell-induced T cell proliferation and IFN-gamma production. J. Immunol. 150, 3755–3765 (1993).
Saraiva, M., Vieira, P. & O’Garra, A. Biology and therapeutic potential of interleukin-10. J. Exp. Med. 217, e20190418 (2020).
Mumm, J. B. et al. IL-10 elicits IFNγ-dependent tumor immune surveillance. Cancer Cell 20, 781–796 (2011).
Qiao, J. et al. Targeting tumors with IL-10 prevents dendritic cell-mediated CD8+ T cell apoptosis. Cancer Cell 35, 901–915.e4 (2019).
Naing, A. et al. PEGylated IL-10 (pegilodecakin) induces systemic immune activation, CD8+ T cell invigoration and polyclonal T cell expansion in cancer patients. Cancer Cell 34, 775–791.e3 (2018).
Emmerich, J. et al. IL-10 directly activates and expands tumor-resident CD8+ T cells without de novo infiltration from secondary lymphoid organs. Cancer Res. 72, 3570–3581 (2012).
Sun, Q. et al. STAT3 regulates CD8+ T cell differentiation and functions in cancer and acute infection. J. Exp. Med. 220, e20220686 (2023). This study shows that STAT3 signalling, primarily activated by IL-10 and IL-21, has a critical role in promoting the functionality and survival of tumour-specific CD8+ T cells, thereby enhancing antitumour responses through both transcriptional and epigenetic regulation.
Guo, Y. et al. Metabolic reprogramming of terminally exhausted CD8+ T cells by IL-10 enhances anti-tumor immunity. Nat. Immunol. 22, 746–756 (2021). This study shows that IL-10 directly enhances the expansion, effector function and metabolic fitness of tumour-specific Tex cells, thereby improving the antitumour efficacy.
Hanna, B. S. et al. Interleukin-10 receptor signaling promotes the maintenance of a PD-1(int) TCF-1+ CD8+ T cell population that sustains anti-tumor immunity. Immunity 54, 2825–2841.e10 (2021).
Marx, A. F. et al. The alarmin interleukin-33 promotes the expansion and preserves the stemness of Tcf-1+ CD8+ T cells in chronic viral infection. Immunity 56, 813–828.e10 (2023).
Feng, B. et al. The type 2 cytokine Fc-IL-4 revitalizes exhausted CD8+ T cells against cancer. Nature 634, 712–720 (2024).
Bai, Z. et al. Single-cell CAR T atlas reveals type 2 function in 8-year leukaemia remission. Nature 634, 702–711 (2024).
Bréart, B. et al. IL-27 elicits a cytotoxic CD8+ T cell program to enforce tumour control. Nature 639, 746–753 (2025).
Danilo, M., Chennupati, V., Silva, J. G., Siegert, S. & Held, W. Suppression of Tcf1 by inflammatory cytokines facilitates effector CD8 T cell differentiation. Cell Rep. 22, 2107–2117 (2018).
Yang, Z. Z. et al. IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma. J. Clin. Invest. 122, 1271–1282 (2012).
Ford, B. R. et al. Tumor microenvironmental signals reshape chromatin landscapes to limit the functional potential of exhausted T cells. Sci. Immunol. 7, eabj9123 (2022).
Bannoud, N. et al. Hypoxia supports differentiation of terminally exhausted CD8 T cells. Front. Immunol. 12, 660944 (2021).
Palazon, A. et al. An HIF-1α/VEGF-A axis in cytotoxic T cells regulates tumor progression. Cancer Cell 32, 669–683.e5 (2017).
Doedens, A. L. et al. Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen. Nat. Immunol. 14, 1173–1182 (2013).
Shen, H. et al. HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells. Nat. Commun. 15, 9394 (2024).
Ma, S. et al. Hypoxia induces HIF1α-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy. Nat. Commun. 13, 4118 (2022).
Vignali, P. D. A. et al. Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity. Nat. Immunol. 24, 267–279 (2023). This study shows that hypoxia promotes CD39 expression in intratumoural CD8+ Tex cells, leading to increased adenosine production and heightened immunosuppression.
Tan, S.-N. et al. Regulatory T cells converted from Th1 cells in tumors suppress cancer immunity via CD39. J. Exp. Med. 222, e20240445 (2025).
Allard, B., Allard, D., Buisseret, L. & Stagg, J. The adenosine pathway in immuno-oncology. Nat. Rev. Clin. Oncol. 17, 611–629 (2020).
Sanders, T. J. et al. Inhibition of ENT1 relieves intracellular adenosine-mediated T cell suppression in cancer. Nat. Immunol. 26, 854–865 (2025).
Klysz, D. D. et al. Inosine induces stemness features in CAR-T cells and enhances potency. Cancer Cell 42, 266–282.e8 (2024).
Chen, C. et al. Mitochondrial metabolic flexibility is critical for CD8+ T cell antitumor immunity. Sci. Adv. 9, eadf9522 (2023).
Wilfahrt, D. & Delgoffe, G. M. Metabolic waypoints during T cell differentiation. Nat. Immunol. 25, 206–217 (2024).
Scharping, N. E. et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat. Immunol. 22, 205–215 (2021).
Yu, Y. R. et al. Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion. Nat. Immunol. 21, 1540–1551 (2020).
Vardhana, S. A. et al. Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen. Nat. Immunol. 21, 1022–1033 (2020). This study, along with Yu et al. (2020), shows that mitochondrial fitness and function are impaired in CD8+ Tex cells, reinforcing their exhausted state.
Ikeda, H. et al. Immune evasion through mitochondrial transfer in the tumour microenvironment. Nature 638, 225–236 (2025).
Baldwin, J. G. et al. Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy. Cell 187, 6614–6630.e21 (2024).
Scharping, N. E. et al. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45, 374–388 (2016).
Bengsch, B. et al. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion. Immunity 45, 358–373 (2016).
Dumauthioz, N. et al. Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity. Cell Mol. Immunol. 18, 1761–1771 (2021).
Sattiraju, A. et al. Hypoxic niches attract and sequester tumor-associated macrophages and cytotoxic T cells and reprogram them for immunosuppression. Immunity 56, 1825–1843.e6 (2023).
Raynor, J. L. & Chi, H. Nutrients: signal 4 in T cell immunity. J. Exp. Med. 221, e20221839 (2024).
Ho, P. C. et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217–1228 (2015). This study, along with Chang et al. (2015), shows that glucose deprivation in the TME suppresses CD8+ T cell function and compromises their antitumour response.
Si, X. et al. Mitochondrial isocitrate dehydrogenase impedes CAR T cell function by restraining antioxidant metabolism and histone acetylation. Cell Metab. 36, 176–192.e10 (2024).
Ma, S., Ming, Y., Wu, J. & Cui, G. Cellular metabolism regulates the differentiation and function of T-cell subsets. Cell Mol. Immunol. 21, 419–435 (2024).
Cao, T. et al. Cancer SLC6A6-mediated taurine uptake transactivates immune checkpoint genes and induces exhaustion in CD8+ T cells. Cell 187, 2288–2304.e27 (2024).
Zhang, Q. et al. Lactobacillus plantarum-derived indole-3-lactic acid ameliorates colorectal tumorigenesis via epigenetic regulation of CD8+ T cell immunity. Cell Metab. 35, 943–960.e9 (2023).
Jia, D. et al. Microbial metabolite enhances immunotherapy efficacy by modulating T cell stemness in pan-cancer. Cell 187, 1651–1665.e21 (2024). This study highlights that the microbial metabolite indole-3-propionic acid increases Tex cell progenitors and enhances the efficacy of PD1 blockade in cancer.
Tang, Y., Chen, Z., Zuo, Q. & Kang, Y. Regulation of CD8+ T cells by lipid metabolism in cancer progression. Cell Mol. Immunol. 21, 1215–1230 (2024).
Miller, K. D. et al. Acetate acts as a metabolic immunomodulator by bolstering T-cell effector function and potentiating antitumor immunity in breast cancer. Nat. Cancer 4, 1491–1507 (2023).
Qiu, J. et al. Acetate promotes T cell effector function during glucose restriction. Cell Rep. 27, 2063–2074.e5 (2019).
Ma, S. et al. Nutrient-driven histone code determines exhausted CD8+ T cell fates. Science 387, eadj3020 (2025). This study highlights changes in nutrient-driven histone modifications during CD8+ T cell exhaustion, where a shift in nutrient preference from acetate to citrate for acetyl-CoA production, through reduced ACSS2 expression and maintained ACLY activity, promotes histone acetylation and gene expression at Tex cell-related loci to drive the exhaustion fate.
Nava Lauson, C. B. et al. Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity. Cell Metab. 35, 633–650.e9 (2023).
Fan, H. et al. Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity. Nature 623, 1034–1043 (2023).
Ma, X. et al. Cholesterol induces CD8+ T cell exhaustion in the tumor microenvironment. Cell Metab. 30, 143–156.e5 (2019).
Yan, C. et al. Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity. Cancer Cell 41, 1276–1293.e11 (2023).
Varanasi, S. K. et al. Bile acid synthesis impedes tumor-specific T cell responses during liver cancer. Science 387, 192–201 (2025).
Soll, D. et al. Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity. Nat. Immunol. 25, 1830–1844 (2024).
Scirgolea, C. et al. NaCl enhances CD8+ T cell effector functions in cancer immunotherapy. Nat. Immunol. 25, 1845–1857 (2024).
Eil, R. et al. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537, 539–543 (2016).
Vodnala, S. K. et al. T cell stemness and dysfunction in tumors are triggered by a common mechanism. Science 363, eaau0135 (2019).
Brand, A. et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 24, 657–671 (2016).
Liu, Y. et al. Activation and antitumor immunity of CD8+ T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid. Sci. Transl. Med. 16, eadk7399 (2024).
Tsai, Y. L. et al. TCR signaling promotes formation of an STS1-Cbl-b complex with pH-sensitive phosphatase activity that suppresses T cell function in acidic environments. Immunity 56, 2682–2698.e9 (2023). This study shows that in the acidic TME, the interaction between the pH-sensitive phosphatase STS1 and the E3 ubiquitin ligase CBL-B suppresses TCR signalling and limits T cell responses.
Johnston, R. J. et al. VISTA is an acidic pH-selective ligand for PSGL-1. Nature 574, 565–570 (2019).
Ma, J. et al. Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria. Nat. Immunol. 25, 552–561 (2024).
Feng, Q. et al. Lactate increases stemness of CD8+ T cells to augment anti-tumor immunity. Nat. Commun. 13, 4981 (2022).
Raychaudhuri, D. et al. Histone lactylation drives CD8+ T cell metabolism and function. Nat. Immunol. 25, 2140–2151 (2024).
Cheng, J. et al. Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment. Cell Metab. 35, 961–978.e10 (2023).
Gu, X. et al. Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion. Nat. Commun. 14, 8154 (2023).
Manzo, T. et al. Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells. J. Exp. Med. 217, e20191920 (2020).
Xu, S. et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors. Immunity 54, 1561–1577.e7 (2021).
Ma, X. et al. CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability. Cell Metab. 33, 1001–1012.e5 (2021). This study, along with Xu et al. (2021), shows that lipid uptake by intratumoural CD8+ T cells through the scavenger receptor CD36 promotes lipid peroxidation and accelerates their exhaustion.
Ping, Y. et al. PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis. Immunity 57, 2122–2139.e9 (2024).
Morotti, M. et al. PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function. Nature 629, 426–434 (2024).
Lacher, S. B. et al. PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells. Nature 629, 417–425 (2024). This study, along with Morotti et al. (2024), shows that tumour cell-derived PGE2 suppresses intratumoural CD8+ T cell effector function and expansion.
Bell, H. N. et al. Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer. Cell Metab. 35, 134–149.e6 (2023).
Zhang, H. et al. Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells. Nat. Cell Biol. 26, 1892–1902 (2024).
Weisshaar, N. et al. The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate. Nat. Immunol. 24, 1921–1932 (2023).
Acharya, N. et al. Endogenous glucocorticoid signaling regulates CD8+ T cell differentiation and development of dysfunction in the tumor microenvironment. Immunity 53, 658–671.e6 (2020).
Hu, C. et al. Tumor-secreted FGF21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8+ T cells. Cell Metab. 36, 630–647.e8 (2024).
Chen, Y. et al. Regulation of CD8+ T memory and exhaustion by the mTOR signals. Cell Mol. Immunol. 20, 1023–1039 (2023).
Staron, M. M. et al. The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8+ T cells during chronic infection. Immunity 41, 802–814 (2014).
Ando, S. et al. mTOR regulates T cell exhaustion and PD-1-targeted immunotherapy response during chronic viral infection. J. Clin. Invest. 133, e160025 (2023).
Mineharu, Y., Kamran, N., Lowenstein, P. R. & Castro, M. G. Blockade of mTOR signaling via rapamycin combined with immunotherapy augments antiglioma cytotoxic and memory T-cell functions. Mol. Cancer Ther. 13, 3024–3036 (2014).
Singleton, D. C., Macann, A. & Wilson, W. R. Therapeutic targeting of the hypoxic tumour microenvironment. Nat. Rev. Clin. Oncol. 18, 751–772 (2021).
Tieu, V. et al. A versatile CRISPR-Cas13d platform for multiplexed transcriptomic regulation and metabolic engineering in primary human T cells. Cell 187, 1278–1295.e20 (2024).
Frisch, A. T. et al. Redirecting glucose flux during in vitro expansion generates epigenetically and metabolically superior T cells for cancer immunotherapy. Cell Metab. 37, 870–885.e8 (2025).
Globig, A. M. et al. The β1-adrenergic receptor links sympathetic nerves to T cell exhaustion. Nature 622, 383–392 (2023). This study highlights that catecholamines released by sympathetic nerves promote CD8+ T cell exhaustion through the β1-adrenergic receptor during chronic infection and cancer.
Wu, V. H. et al. The GPCR-Gαs-PKA signaling axis promotes T cell dysfunction and cancer immunotherapy failure. Nat. Immunol. 24, 1318–1330 (2023).
Zhang, B. et al. B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity. Nature 599, 471–476 (2021).
Tian, J., Chau, C., Hales, T. G. & Kaufman, D. L. GABAA receptors mediate inhibition of T cell responses. J. Neuroimmunol. 96, 21–28 (1999).
Wang, X. et al. A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity. Mol. Cell 84, 760–775.e7 (2024).
Balood, M. et al. Nociceptor neurons affect cancer immunosurveillance. Nature 611, 405–412 (2022).
Ravindranathan, S. et al. Targeting vasoactive intestinal peptide-mediated signaling enhances response to immune checkpoint therapy in pancreatic ductal adenocarcinoma. Nat. Commun. 13, 6418 (2022).
Yin, T. et al. Breaking NGF-TrkA immunosuppression in melanoma sensitizes immunotherapy for durable memory T cell protection. Nat. Immunol. 25, 268–281 (2024).
Wiedeman, A. E. et al. Autoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progression. J. Clin. Invest. 130, 480–490 (2020).
McKinney, E. F., Lee, J. C., Jayne, D. R., Lyons, P. A. & Smith, K. G. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature 523, 612–616 (2015).
Gearty, S. V. et al. An autoimmune stem-like CD8 T cell population drives type 1 diabetes. Nature 602, 156–161 (2022). This study shows that in type 1 diabetes, islet-specific CD8+ T cells expressing inhibitory receptors include a stem-like subset located in the pancreatic draining lymph nodes, which continuously migrates into the islets and drives disease progression.
Long, S. A. et al. Partial exhaustion of CD8 T cells and clinical response to teplizumab in new-onset type 1 diabetes. Sci. Immunol. 1, eaai7793 (2016).
Okazaki, T. et al. PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice. J. Exp. Med. 208, 395–407 (2011).
Grebinoski, S. et al. Autoreactive CD8+ T cells are restrained by an exhaustion-like program that is maintained by LAG3. Nat. Immunol. 23, 868–877 (2022).
Ben Nasr, M. et al. Glucagon-like peptide 1 receptor is a T cell-negative costimulatory molecule. Cell Metab. 36, 1302–1319.e12 (2024).
Lee, K. A. et al. Characterization of age-associated exhausted CD8+ T cells defined by increased expression of Tim-3 and PD-1. Aging Cell 15, 291–300 (2016).
Han, S., Georgiev, P., Ringel, A. E., Sharpe, A. H. & Haigis, M. C. Age-associated remodeling of T cell immunity and metabolism. Cell Metab. 35, 36–55 (2023).
Durand, A. et al. Type 1 interferons and Foxo1 down-regulation play a key role in age-related T-cell exhaustion in mice. Nat. Commun. 15, 1718 (2024).
Chen, A. C. Y. et al. The aged tumor microenvironment limits T cell control of cancer. Nat. Immunol. 25, 1033–1045 (2024).
Zhivaki, D. et al. Correction of age-associated defects in dendritic cells enables CD4+ T cells to eradicate tumors. Cell 187, 3888–3903.e18 (2024).
Zhang, J. et al. Osr2 functions as a biomechanical checkpoint to aggravate CD8+ T cell exhaustion in tumor. Cell 187, 3409–3426.e24 (2024).
Pang, R. et al. PIEZO1 mechanically regulates the antitumour cytotoxicity of T lymphocytes. Nat. Biomed. Eng. 8, 1162–1176 (2024).
Schnell, A. et al. Targeting PGLYRP1 promotes antitumor immunity while inhibiting autoimmune neuroinflammation. Nat. Immunol. 24, 1908–1920 (2023).
Tanaka, A. & Sakaguchi, S. Regulatory T cells in cancer immunotherapy. Cell Res. 27, 109–118 (2017).
Zhou, L. et al. Spatial and functional targeting of intratumoral Tregs reverses CD8+ T cell exhaustion and promotes cancer immunotherapy. J. Clin. Invest. 134, e180080 (2024).
Solomon, I. et al. CD25-Treg-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity. Nat. Cancer 1, 1153–1166 (2020).
Cabrita, R. et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 577, 561–565 (2020).
Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020).
Fridman, W. H. et al. Tertiary lymphoid structures and B cells: an intratumoral immunity cycle. Immunity 56, 2254–2269 (2023).
Im, S. J. et al. Characteristics and anatomic location of PD-1+TCF1+ stem-like CD8 T cells in chronic viral infection and cancer. Proc. Natl Acad. Sci. USA 120, e2221985120 (2023).
Gaglia, G. et al. Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma. Cancer Cell 41, 871–886.e10 (2023).
Magen, A. et al. Intratumoral dendritic cell-CD4+ T helper cell niches enable CD8+ T cell differentiation following PD-1 blockade in hepatocellular carcinoma. Nat. Med. 29, 1389–1399 (2023).
Espinosa-Carrasco, G. et al. Intratumoral immune triads are required for immunotherapy-mediated elimination of solid tumors. Cancer Cell 42, 1202–1216.e8 (2024). This study highlights that within tumours, CD4+ T cells engage with CD8+ T cells on the same dendritic cell to license CD8+ T cell cytotoxicity and promote cancer cell elimination.
Shi, H., Doench, J. G. & Chi, H. CRISPR screens for functional interrogation of immunity. Nat. Rev. Immunol. 23, 363–380 (2023).
Mognol, G. P. et al. Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells. Proc. Natl Acad. Sci. USA 114, E2776–E2785 (2017).
Scott-Browne, J. P. et al. Dynamic changes in chromatin accessibility occur in CD8+ T cells responding to viral infection. Immunity 45, 1327–1340 (2016).
Tille, L. et al. Activation of the transcription factor NFAT5 in the tumor microenvironment enforces CD8+ T cell exhaustion. Nat. Immunol. 24, 1645–1653 (2023).
Srirat, T. et al. NR4a1/2 deletion promotes accumulation of TCF1+ stem-like precursors of exhausted CD8+ T cells in the tumor microenvironment. Cell Rep. 43, 113898 (2024).
Hao, J. et al. NR4A1 transcriptionally regulates the differentiation of stem-like CD8+ T cells in the tumor microenvironment. Cell Rep. 43, 114301 (2024).
Huang, Y. J. et al. Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate. Sci. Immunol. 10, eado3032 (2025).
Gounari, F. & Khazaie, K. TCF-1: a maverick in T cell development and function. Nat. Immunol. 23, 671–678 (2022).
Abadie, K. et al. Reversible, tunable epigenetic silencing of TCF1 generates flexibility in the T cell memory decision. Immunity 57, 271–286.e13 (2024).
Zhou, X. et al. Differentiation and persistence of memory CD8+ T cells depend on T cell factor 1. Immunity 33, 229–240 (2010).
Shan, Q. et al. Tcf1 preprograms the mobilization of glycolysis in central memory CD8+ T cells during recall responses. Nat. Immunol. 23, 386–398 (2022).
Sade-Feldman, M. et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175, 998–1013.e20 (2018).
Chen, Z. et al. TCF-1-centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision. Immunity 51, 840–855.e5 (2019).
Escobar, G. et al. Tumor immunogenicity dictates reliance on TCF1 in CD8+ T cells for response to immunotherapy. Cancer Cell 41, 1662–1679.e7 (2023).
Ichii, H. et al. Role for Bcl-6 in the generation and maintenance of memory CD8+ T cells. Nat. Immunol. 3, 558–563 (2002).
Leong, Y. A. et al. CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles. Nat. Immunol. 17, 1187–1196 (2016). This study highlights the critical roles of multiple transcription factors, including BCL6, BLIMP1, TCF1, ID2, ID3 and E2A, in regulating the differentiation of CXCR5+CD8+ T cells during chronic viral infection.
He, R. et al. Follicular CXCR5-expressing CD8+ T cells curtail chronic viral infection. Nature 537, 412–428 (2016). This study, along with Im et al. (2016) and Leong et al. (2016), shows that CXCR5+CD8+ T cells represent a key population with strong proliferative potential and sustained antiviral activity during chronic viral infection.
Kallies, A., Xin, A., Belz, G. T. & Nutt, S. L. Blimp-1 transcription factor is required for the differentiation of effector CD8+ T cells and memory responses. Immunity 31, 283–295 (2009).
Rutishauser, R. L. et al. Transcriptional repressor Blimp-1 promotes CD8+ T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity 31, 296–308 (2009).
Xin, A. et al. A molecular threshold for effector CD8+ T cell differentiation controlled by transcription factors Blimp-1 and T-bet. Nat. Immunol. 17, 422–432 (2016).
Sawant, D. V. et al. Adaptive plasticity of IL-10+ and IL-35+ Treg cells cooperatively promotes tumor T cell exhaustion. Nat. Immunol. 20, 724–735 (2019).
Chihara, N. et al. Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature 558, 454–459 (2018).
Shin, H. et al. A role for the transcriptional repressor Blimp-1 in CD8+ T cell exhaustion during chronic viral infection. Immunity 31, 309–320 (2009). This study demonstrates that BLIMP1 has a critical role in promoting inhibitory receptor expression in CD8+ T cells during their exhaustion in chronic viral infection.
Giordano, M. et al. Molecular profiling of CD8 T cells in autochthonous melanoma identifies Maf as driver of exhaustion. EMBO J. 34, 2042–2058 (2015).
Jung, I. Y. et al. BLIMP1 and NR4A3 transcription factors reciprocally regulate antitumor CAR T cell stemness and exhaustion. Sci. Transl. Med. 14, eabn7336 (2022).
Dai, X. et al. Massively parallel knock-in engineering of human T cells. Nat. Biotechnol. 41, 1239–1255 (2023).
Yang, R. et al. IL-6 promotes the differentiation of a subset of naive CD8+ T cells into IL-21-producing B helper CD8+ T cells. J. Exp. Med. 213, 2281–2291 (2016).
Siegel, A. M. et al. A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory. Immunity 35, 806–818 (2011).
Vahedi, G. et al. STATs shape the active enhancer landscape of T cell populations. Cell 151, 981–993 (2012).
Beltra, J. C. et al. Stat5 opposes the transcription factor Tox and rewires exhausted CD8+ T cells toward durable effector-like states during chronic antigen exposure. Immunity 56, 2699–2718.e11 (2023). This study demonstrates the critical role of STAT5 in promoting an effector-like state of Tex cells, enhancing their effector function and expansion during chronic viral infection and cancer.
Grange, M. et al. Activated STAT5 promotes long-lived cytotoxic CD8+ T cells that induce regression of autochthonous melanoma. Cancer Res. 72, 76–87 (2012).
Zhou, J. et al. The ubiquitin ligase MDM2 sustains STAT5 stability to control T cell-mediated antitumor immunity. Nat. Immunol. 22, 460–470 (2021).
Zheng, Y. et al. An engineered viral protein activates STAT5 to prevent T cell suppression. Sci. Immunol. 10, eadn9633 (2025).
Ding, Z. C. et al. Persistent STAT5 activation reprograms the epigenetic landscape in CD4+ T cells to drive polyfunctionality and antitumor immunity. Sci. Immunol. 5, eaba5962 (2020).
Chen, Y. et al. CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance. Nat. Commun. 10, 4415 (2019).
Lee, J. et al. IL-15 promotes self-renewal of progenitor exhausted CD8 T cells during persistent antigenic stimulation. Front. Immunol. 14, 1117092 (2023).
Yao, C. et al. BACH2 enforces the transcriptional and epigenetic programs of stem-like CD8+ T cells. Nat. Immunol. 22, 370–380 (2021).
Gautam, S. et al. The transcription factor c-Myb regulates CD8+ T cell stemness and antitumor immunity. Nat. Immunol. 20, 337–349 (2019).
Utzschneider, D. T. et al. Active maintenance of T cell memory in acute and chronic viral infection depends on continuous expression of FOXO1. Cell Rep. 22, 3454–3467 (2018).
Tsui, C. et al. MYB orchestrates T cell exhaustion and response to checkpoint inhibition. Nature 609, 354–360 (2022).
Ran, L. et al. The transcription regulator ID3 maintains tumor-specific memory CD8+ T cells in draining lymph nodes during tumorigenesis. Cell Rep. 43, 114690 (2024).
Gago da Graça, C. et al. Stem-like memory and precursors of exhausted T cells share a common progenitor defined by ID3 expression. Sci. Immunol. 10, eadn1945 (2025).
Utzschneider, D. T. et al. Early precursor T cells establish and propagate T cell exhaustion in chronic infection. Nat. Immunol. 21, 1256–1266 (2020).
Li, J., He, Y., Hao, J., Ni, L. & Dong, C. High levels of eomes promote exhaustion of anti-tumor CD8+ T cells. Front. Immunol. 9, 2981 (2018).
Doering, T. A. et al. Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity 37, 1130–1144 (2012).
Paley, M. A. et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 338, 1220–1225 (2012).
Li, Y. et al. Id2 epigenetically controls CD8+ T-cell exhaustion by disrupting the assembly of the Tcf3-LSD1 complex. Cell Mol. Immunol. 21, 292–308 (2024).
Chen, Y. et al. BATF regulates progenitor to cytolytic effector CD8+ T cell transition during chronic viral infection. Nat. Immunol. 22, 996–1007 (2021).
Beltra, J.-C. et al. Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity 52, 825–841.e8 (2020).
Zhang, X. et al. Depletion of BATF in CAR-T cells enhances antitumor activity by inducing resistance against exhaustion and formation of central memory cells. Cancer Cell 40, 1407–1422.e7 (2022).
Man, K. et al. Transcription factor IRF4 promotes CD8+ T cell exhaustion and limits the development of memory-like T cells during chronic infection. Immunity 47, 1129–1141.e5 (2017).
Wei, J. et al. Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy. Nature 576, 471–476 (2019).
Zhou, P. et al. Single-cell CRISPR screens in vivo map T cell fate regulomes in cancer. Nature 624, 154–163 (2023). This study, using an in vivo single-cell CRISPR screen strategy, identifies IKAROS and ETS1 as critical regulators of the differentiation of Tex cell progenitors into intermediate Tex cells, while the RBPJ–IRF1 axis promotes the differentiation from intermediate to terminal Tex cells.
Rudloff, M. W. et al. Hallmarks of CD8+ T cell dysfunction are established within hours of tumor antigen encounter before cell division. Nat. Immunol. 24, 1527–1539 (2023).
Yates, K. B. et al. Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans. Nat. Immunol. 22, 1020–1029 (2021).
Ghoneim, H. E. et al. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell 170, 142–157.e19 (2017). This study shows that during exhaustion, CD8+ T cells acquire de novo DNA methylation that promotes terminal exhaustion and limits their rejuvenation by PD1 or PDL1 blockade.
Abdel-Hakeem, M. S. et al. Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation. Nat. Immunol. 22, 1008–1019 (2021).
Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016).
Sen, D. R. et al. The epigenetic landscape of T cell exhaustion. Science 354, 1165–1169 (2016).
Youngblood, B. et al. Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8+ T cells. Immunity 35, 400–412 (2011).
Weiss, S. A. et al. Epigenetic tuning of PD-1 expression improves exhausted T cell function and viral control. Nat. Immunol. 25, 1871–1883 (2024).
Jadhav, R. R. et al. Epigenetic signature of PD-1+ TCF1+ CD8 T cells that act as resource cells during chronic viral infection and respond to PD-1 blockade. Proc. Natl Acad. Sci. USA 116, 14113–14118 (2019).
Zebley, C. C. et al. CD19-CAR T cells undergo exhaustion DNA methylation programming in patients with acute lymphoblastic leukemia. Cell Rep. 37, 110079 (2021).
Kang, T. G. et al. Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy. Science 386, eadl4492 (2024).
Liu, Y. et al. LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade. Nat. Commun. 12, 6831 (2021).
Dimitri, A. J. et al. TET2 regulates early and late transitions in exhausted CD8+ T cell differentiation and limits CAR T cell function. Sci. Adv. 10, eadp9371 (2024).
Gennert, D. G. et al. Dynamic chromatin regulatory landscape of human CAR T cell exhaustion. Proc. Natl Acad. Sci. USA 118, e2104758118 (2021).
Ahmad, K., Brahma, S. & Henikoff, S. Epigenetic pioneering by SWI/SNF family remodelers. Mol. Cell 84, 194–201 (2024).
Guo, A. et al. cBAF complex components and MYC cooperate early in CD8+ T cell fate. Nature 607, 135–141 (2022).
McDonald, B. et al. Canonical BAF complex activity shapes the enhancer landscape that licenses CD8+ T cell effector and memory fates. Immunity 56, 1303–1319.e5 (2023).
Battistello, E. et al. Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion. Mol. Cell 83, 1216–1236.e2 (2023).
Belk, J. A. et al. Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence. Cancer Cell 40, 768–786.e7 (2022).
Baxter, A. E. et al. The SWI/SNF chromatin remodeling complexes BAF and PBAF differentially regulate epigenetic transitions in exhausted CD8+ T cells. Immunity 56, 1320–1340.e10 (2023).
Kharel, A. et al. Loss of PBAF promotes expansion and effector differentiation of CD8+ T cells during chronic viral infection and cancer. Cell Rep. 42, 112649 (2023). This study, along with Battistello et al. (2023), Belk et al. (2022) and Baxter et al. (2023), shows that the SWI/SNF family member cBAF promotes effector-like differentiation of Tex cells while suppressing their stemness, whereas PBAF supports the maintenance of dominant Tex cell progenitors.
Wang, L. et al. PROTAC-mediated NR4A1 degradation as a novel strategy for cancer immunotherapy. J. Exp. Med. 221, e20231519 (2024).
Prinzing, B. et al. Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity. Sci. Transl. Med. 13, eabh0272 (2021).
Lynn, R. C. et al. c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature 576, 293–300 (2019).
Seo, H. et al. BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells. Nat. Immunol. 22, 983–995 (2021).
McCutcheon, S. R. et al. Transcriptional and epigenetic regulators of human CD8+ T cell function identified through orthogonal CRISPR screens. Nat. Genet. 55, 2211–2223 (2023).
Doan, A. E. et al. FOXO1 is a master regulator of memory programming in CAR T cells. Nature 629, 211–218 (2024).
Shan, Q. et al. Ectopic Tcf1 expression instills a stem-like program in exhausted CD8+ T cells to enhance viral and tumor immunity. Cell Mol. Immunol. 18, 1262–1277 (2021).
Chan, J. D. et al. FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy. Nature 629, 201–210 (2024). This study, together with Doan et al. (2024), shows that FOXO1 overexpression in CAR T cells enhances their stemness, metabolic fitness, persistence and antitumour efficacy.
Moynihan, K. D. et al. IL2 targeted to CD8+ T cells promotes robust effector T-cell responses and potent antitumor immunity. Cancer Discov. 14, 1206–1225 (2024).
Zhu, W. et al. A novel engineered IL-21 receptor arms T-cell receptor-engineered T cells (TCR-T cells) against hepatocellular carcinoma. Signal. Transduct. Target. Ther. 9, 101 (2024).
Huang, Z. et al. IL-27 promotes the expansion of self-renewing CD8+ T cells in persistent viral infection. J. Exp. Med. 216, 1791–1808 (2019).
Zhao, Y. et al. IL-10-expressing CAR T cells resist dysfunction and mediate durable clearance of solid tumors and metastases. Nat. Biotechnol. 42, 1693–1704 (2024).
Pallavicini, I. et al. LSD1 inhibition improves efficacy of adoptive T cell therapy by enhancing CD8+ T cell responsiveness. Nat. Commun. 15, 7366 (2024).
Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015).
Crawford, A. et al. Molecular and transcriptional basis of CD4+ T cell dysfunction during chronic infection. Immunity 40, 289–302 (2014).
Dong, Y. et al. CD4+ T cell exhaustion revealed by high PD-1 and LAG-3 expression and the loss of helper T cell function in chronic hepatitis B. BMC Immunol. 20, 27 (2019).
Kaufmann, D. E. et al. Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nat. Immunol. 8, 1246–1254 (2007).
Miggelbrink, A. M. et al. CD4 T-cell exhaustion: does it exist and what are its roles in cancer? Clin. Cancer Res. 27, 5742–5752 (2021).
Tracy, S. I. et al. Combining nilotinib and PD-L1 blockade reverses CD4+ T-cell dysfunction and prevents relapse in acute B-cell leukemia. Blood 140, 335–348 (2022).
Aljobaily, N. et al. Autoimmune CD4+ T cells fine-tune TCF1 expression to maintain function and survive persistent antigen exposure during diabetes. Immunity 57, 2583–2596.e6 (2024).
Saggau, C. et al. Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases. Immunity 57, 2416–2432.e8 (2024). This study, along with Aljobaily et al. (2024), demonstrates that autoimmune CD4+ T cells exhibit an exhaustion phenotype and persist in both mouse and human autoimmune diseases.
Xia, Y. et al. BCL6-dependent TCF-1+ progenitor cells maintain effector and helper CD4+ T cell responses to persistent antigen. Immunity 55, 1200–1215.e6 (2022).
Kim, M. Y. et al. A long-acting interleukin-7, rhIL-7-hyFc, enhances CAR T cell expansion, persistence, and anti-tumor activity. Nat. Commun. 13, 3296 (2022).
Steffin, D. et al. Interleukin-15-armoured GPC3 CAR T cells for patients with solid cancers. Nature 637, 940–946 (2025).
Beck, J. D. et al. Long-lasting mRNA-encoded interleukin-2 restores CD8+ T cell neoantigen immunity in MHC class I-deficient cancers. Cancer Cell 42, 568–582.e11 (2024).
Leonard, W. J., Lin, J. X. & O’Shea, J. J. The γc family of cytokines: basic biology to therapeutic ramifications. Immunity 50, 832–850 (2019).
Li, Y. et al. Multifunctional oncolytic nanoparticles deliver self-replicating IL-12 RNA to eliminate established tumors and prime systemic immunity. Nat. Cancer 1, 882–893 (2020).
Saxton, R. A., Glassman, C. R. & Garcia, K. C. Emerging principles of cytokine pharmacology and therapeutics. Nat. Rev. Drug Discov. 22, 21–37 (2023).
Hernandez, R., Põder, J., LaPorte, K. M. & Malek, T. R. Engineering IL-2 for immunotherapy of autoimmunity and cancer. Nat. Rev. Immunol. 22, 614–628 (2022).
Sockolosky, J. T. et al. Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes. Science 359, 1037–1042 (2018).
Zhang, Q. et al. A human orthogonal IL-2 and IL-2Rβ system enhances CAR T cell expansion and antitumor activity in a murine model of leukemia. Sci. Transl. Med. 13, eabg6986 (2021).
Piper, M. et al. Simultaneous targeting of PD-1 and IL-2Rβγ with radiation therapy inhibits pancreatic cancer growth and metastasis. Cancer Cell 41, 950–969.e6 (2023).
Codarri Deak, L. et al. PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells. Nature 610, 161–172 (2022).
Rakhshandehroo, T. et al. A CAR enhancer increases the activity and persistence of CAR T cells. Nat. Biotechnol. 43, 948–959 (2025).
Mitra, S. et al. Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps. Immunity 42, 826–838 (2015).
Mo, F. et al. An engineered IL-2 partial agonist promotes CD8+ T cell stemness. Nature 597, 544–548 (2021). This study shows that H9T, an engineered IL-2 partial agonist with enhanced affinity for IL-2Rβ and reduced binding to IL-2Rγ, modulates STAT5 signalling in CD8+ T cells to promote their expansion and antitumour activity while supporting the maintenance of a stem-like state.
Horton, B. L. et al. Overcoming lung cancer immunotherapy resistance by combining nontoxic variants of IL-12 and IL-2. JCI Insight 8, e172728 (2023).
Kalbasi, A. et al. Potentiating adoptive cell therapy using synthetic IL-9 receptors. Nature 607, 360–365 (2022).
Acknowledgements
This work was supported by grants from Natural Science Foundation of China (31991173 and 31991170), National Key Research and Development Program of China (2021YFC2302403), CAMS Innovation Fund for Medical Sciences (2022-I2M-5-01). C.D. acknowledges receipt of a New Cornerstone Investigator award.
Author information
Authors and Affiliations
Contributions
Both authors contributed equally to all aspects of article preparation.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Reviews Immunology thanks Gordon Freeman, Marco Ongaro, Grégory Verdeil and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Sun, Q., Dong, C. Regulators of CD8+ T cell exhaustion. Nat Rev Immunol (2025). https://doi.org/10.1038/s41577-025-01221-x
Accepted:
Published:
Version of record:
DOI: https://doi.org/10.1038/s41577-025-01221-x