T-cell exhaustion from a multiomics perspective: Differentiation mechanisms and regulatory networks in the journey from progenitor-Exhausted T cells to terminally exhausted T cells

Abstract

A central hurdle limiting the success of T-cell-based immunotherapies is the progressive dysfunction of T cells, known as exhaustion. Overcoming this exhausted state is therefore a pivotal objective in translational oncology and immunology. The advent of single-cell multiomics has fundamentally revised the once-prevailing view of exhaustion as a uniform endpoint. Instead, it is now recognised as a dynamic differentiation process comprising a spectrum of distinct cellular states. This spectrum is organised along a hierarchical axis, originating from progenitor-exhausted (Tpex) cells that retain proliferative potential and advancing towards terminally exhausted (Tex) populations with severely impaired effector functions. We undertake a comprehensive synthesis of multiomics data—spanning transcriptomic, epigenomic, metabolomic, proteomic and posttranslational modification (PTM)-proteomic layers—to decipher the interconnected regulatory programmes that dictate commitment along this exhaustion axis. From this integrated analysis, we derive a unified mechanistic framework that delineates the molecular drivers of Tpex cell fate determination and terminal exhaustion. Beyond its explanatory power for basic biology, this framework serves as a direct roadmap for therapeutic innovation, highlighting novel nodes for intervention aimed at reinvigorating the exhausted T-cell compartment. The practical application of these insights holds significant promise for enhancing the efficacy of established current immunotherapeutic platforms.

Keywords

T-cell exhaustion / single-cell multiomics / Tpex / terminally exhausted T cells / transcriptomics / epigenomics / metabolomics / proteomics / PTM proteomics / cancer immunotherapy

References

[1] Wherry EJ. T cell exhaustion. Nat Immunol. 2011; 12(6): 492-499.

[2] McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T cell exhaustion during chronic viral infection and cancer. Annu Rev Immunol. 2019; 37: 457-495.

[3] Kuchroo JR, Hafler DA, Sharpe AH, Lucca LE. The double-edged sword: harnessing PD-1 blockade in tumor and autoimmunity. Sci Immunol. 2021; 6(65):eabf4034.

[4] Baessler A, Vignali DAA. T cell exhaustion. Annu Rev Immunol. 2024; 42(1): 179-206.

[5] Wherry EJ, Ha SJ, Kaech SM, et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity. 2007; 27(4): 670-684.

[6] Sun Q, Dong C. Regulators of CD8(+) T cell exhaustion. Nat Rev Immunol. 2026; 26(2): 129-151.

[7] Sen DR, Kaminski J, Barnitz RA, et al. The epigenetic landscape of T cell exhaustion. Science. 2016; 354(6316): 1165-1169.

[8] Itahashi K, Irie T, Yuda J, et al. BATF epigenetically and transcriptionally controls the activation program of regulatory T cells in human tumors. Sci Immunol. 2022; 7(76):eabk0957.

[9] Belk JA, Daniel B, Satpathy AT. Epigenetic regulation of T cell exhaustion. Nat Immunol. 2022; 23(6): 848-860.

[10] Yao C, Sun HW, Lacey NE, et al. Single-cell RNA-seq reveals TOX as a key regulator of CD8(+) T cell persistence in chronic infection. Nat Immunol. 2019; 20(7): 890-901.

[11] Miller BC, Sen DR, Al Abosy R, et al. Subsets of exhausted CD8(+) T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol. 2019; 20(3): 326-336.

[12] Paley MA, Kroy DC, Odorizzi PM, et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science. 2012; 338(6111): 1220-1225.

[13] Xing S, Li F, Zeng Z, et al. Tcf1 and Lef1 transcription factors establish CD8(+) T cell identity through intrinsic HDAC activity. Nat Immunol. 2016; 17(6): 695-703.

[14] Gounari F, Khazaie K. TCF-1: a maverick in T cell development and function. Nat Immunol. 2022; 23(5): 671-678.

[15] Wang Y, Hu J, Li Y, et al. The transcription factor TCF1 preserves the effector function of exhausted CD8 T cells during chronic viral infection. Front Immunol. 2019; 10: 169.

[16] Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015; 15(8): 486-499.

[17] Yi M, Niu M, Xu L, Luo S, Wu K. Regulation of PD-L1 expression in the tumor microenvironment. J Hematol Oncol. 2021; 14(1): 10.

[18] West EE, Jin HT, Rasheed AU, et al. PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. J Clin Invest. 2013; 123(6): 2604-2615.

[19] Chen J, López-Moyado IF, Seo H, et al. NR4A transcription factors limit CAR T cell function in solid tumours. Nature. 2019; 567(7749): 530-534.

[20] Chen B, Li Y, Wang H. Recent process of using nanoparticles in the T cell-based immunometabolic therapy. Nanotec Rev. 2024; 13(1).

[21] Shan Q, Hu S, Chen X, et al. Ectopic Tcf1 expression instills a stem-like program in exhausted CD8(+) T cells to enhance viral and tumor immunity. Cell Mol Immunol. 2021; 18(5): 1262-1277.

[22] LaFleur MW, Nguyen TH, Coxe MA, et al. PTPN2 regulates the generation of exhausted CD8(+) T cell subpopulations and restrains tumor immunity. Nat Immunol. 2019; 20(10): 1335-1347.

[23] He R, Hou S, Liu C, et al. Follicular CXCR5- expressing CD8(+) T cells curtail chronic viral infection. Nature. 2016; 537(7620): 412-428.

[24] Alfei F, Kanev K, Hofmann M, et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature. 2019; 571(7764): 265-269.

[25] Khan O, Giles JR, McDonald S, et al. TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion. Nature. 2019; 571(7764): 211-218.

[26] Liu Q, Li J, Sun X, et al. Immunosenescence and cancer: molecular hallmarks, tumor microenvironment remodeling, and age-specific immunotherapy challenges. J Hematol Oncol. 2025; 18(1): 81.

[27] Jobin K, Seetharama D, Rüttger L, et al. A distinct priming phase regulates CD8 T cell immunity by orchestrating paracrine IL-2 signals. Science. 2025; 388(6743):eadq1405.

[28] Kallies A, Zehn D, Utzschneider DT. Precursor exhausted T cells: key to successful immunotherapy?. Nat Rev Immunol. 2020; 20(2): 128-136.

[29] Blank CU, Haining WN, Held W, et al. Defining 'T cell exhaustion. Nat Rev Immunol. 2019; 19(11): 665-674.

[30] Buck MD, O'Sullivan D, Klein Geltink RI, et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell. 2016; 166(1): 63-76.

[31] Yang JF, Xing X, Luo L, et al. Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8(+) T cell metabolic fitness and function in tumors. Sci Immunol. 2023; 8(87):eabq2424.

[32] Siska PJ, Beckermann KE, Mason FM, et al. Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI Insight. 2017; 2(12):e93411.

[33] Bengsch B, Johnson AL, Kurachi M, 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. 2016; 45(2): 358-373.

[34] Grandi FC, Modi H, Kampman L, Corces MR. Chromatin accessibility profiling by ATAC-seq. Nat Protoc. 2022; 17(6): 1518-1552.

[35] Huang YJ, Ngiow SF, Baxter AE, et al. Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate. Sci Immunol. 2025; 10(105):eado3032.

[36] Giles JR, Ngiow SF, Manne S, 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. 2022; 23(11): 1600-1613.

[37] Ghoneim HE, Fan Y, Moustaki A, et al. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell. 2017; 170(1): 142-157.e19.

[38] Buquicchio FA, Fonseca R, Yan PK, et al. Distinct epigenomic landscapes underlie tissue-specific memory T cell differentiation. Immunity. 2024; 57(9): 2202-2215.e6.

[39] Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002; 16(1): 6-21.

[40] Abdel-Hakeem MS, Manne S, Beltra JC, et al. Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation. Nat Immunol. 2021; 22(8): 1008-1019.

[41] Li X, Li Y, Dong L, et al. Decitabine priming increases anti-PD-1 antitumor efficacy by promoting CD8+ progenitor exhausted T cell expansion in tumor models. J Clin Invest. 2023; 133(7):e165673.

[42] Hansen KH, Bracken AP, Pasini D, et al. A model for transmission of the H3K27me3 epigenetic mark. Nat Cell Biol. 2008; 10(11): 1291-1300.

[43] Scott AC, Dündar F, Zumbo P, et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature. 2019; 571(7764): 270-274.

[44] Minnie SA, Waltner OG, Zhang P, et al. TIM-3(+) CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies. Sci Immunol. 2024; 9(94):eadg1094.

[45] Shakiba M, Zumbo P, Espinosa-Carrasco G, et al. TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion. J Exp Med. 2022; 219(2):e20201966.

[46] Pichler AC, Carrié N, Cuisinier M, et al. TCR-independent CD137 (4-1BB) signaling promotes CD8(+)-exhausted T cell proliferation and terminal differentiation. Immunity. 2023; 56(7): 1631-1648.e10.

[47] Peralta RM, Xie B, Lontos K, et al. Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism. Nat Immunol. 2024; 25(12): 2297-2307.

[48] Scharping NE, Menk AV, Moreci RS, et al. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity. 2016; 45(2): 374-388.

[49] Zarour HM. Reversing T-cell dysfunction and exhaustion in cancer. Clin Cancer Res. 2016; 22(8): 1856-1864.

[50] Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front Oncol. 2018; 8: 86.

[51] Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009; 10(1): 29-37.

[52] Tinoco R, Alcalde V, Yang Y, Sauer K, Zuniga EI. Cell-intrinsic transforming growth factor-beta signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo. Immunity. 2009; 31(1): 145-157.

[53] Hashimoto M, Araki K, Cardenas MA, et al. PD-1 combination therapy with IL-2 modifies CD8(+) T cell exhaustion program. Nature. 2022; 610(7930): 173-181.

[54] Sun Q, Zhao X, Li R, et al. STAT3 regulates CD8+ T cell differentiation and functions in cancer and acute infection. J Exp Med. 2023; 220(4):e20220686.

[55] Hanna BS, Llaó-Cid L, Iskar M, 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. 2021; 54(12): 2825-2841.e10.

[56] Feng B, Bai Z, Zhou X, et al. The type 2 cytokine Fc-IL-4 revitalizes exhausted CD8(+) T cells against cancer. Nature. 2024; 634(8034): 712-720.

[57] Yang ZZ, Grote DM, Ziesmer SC, 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. 2012; 122(4): 1271-1282.

[58] Chen W, Teo JMN, Yau SW, et al. Chronic type I interferon signaling promotes lipid-peroxidation-driven terminal CD8(+) T cell exhaustion and curtails anti-PD-1 efficacy. Cell Rep. 2022; 41(7):111647.

[59] Messmer JM, Effern M, Hölzel M. From Tpex to Tex: a journey through CD8(+) T cell responses in cancer immunotherapy. Signal Transduct Target Ther. 2023; 8(1): 331.

[60] Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 2015; 36(4): 265-276.

[61] Chen Y, Xu Z, Sun H, et al. Regulation of CD8(+) T memory and exhaustion by the mTOR signals. Cell Mol Immunol. 2023; 20(9): 1023-1039.

[62] Rica R, Waldherr M, Miyakoda E, et al. HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection. J Exp Med. 2025; 222(8):e20240829.

[63] Hudson WH, Gensheimer J, Hashimoto M, 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. 2019; 51(6): 1043-1058.e4.

[64] Beltra JC, Manne S, Abdel-Hakeem MS, et al. Developmental relationships of four exhausted CD8(+) T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity. 2020; 52(5): 825-841.e8.

[65] Chen Z, Ji Z, Ngiow SF, et al. TCF-1-centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision. Immunity. 2019; 51(5): 840-855.e5.

[66] Paley MA, Wherry EJ. TCF-1 flips the switch on Eomes. Immunity. 2010; 33(2): 145-147.

[67] Gautam S, Fioravanti J, Zhu W, et al. The transcription factor c-Myb regulates CD8(+) T cell stemness and antitumor immunity. Nat Immunol. 2019; 20(3): 337-349.

[68] Kaech SM, Cui W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol. 2012; 12(11): 749-761.

[69] Li P, Leonard WJ. Chromatin accessibility and interactions in the transcriptional regulation of T cells. Front Immunol. 2018; 9: 2738.

[70] Iyer NG, Ozdag H, Caldas C. p300/CBP and cancer. Oncogene. 2004; 23(24): 4225-4231.

[71] Macian F. NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol. 2005; 5(6): 472-484.

[72] Martinez GJ, Pereira RM, Äijö T, et al. The transcription factor NFAT promotes exhaustion of activated CD8⁺ T cells. Immunity. 2015; 42(2): 265-278.

[73] Seo H, Chen J, González-Avalos E, et al. TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8(+) T cell exhaustion. Proc Natl Acad Sci U S A. 2019; 116(25): 12410-12415.

[74] Wang X, He Q, Shen H, et al. TOX promotes the exhaustion of antitumor CD8(+) T cells by preventing PD1 degradation in hepatocellular carcinoma. J Hepatol. 2019; 71(4): 731-741.

[75] Bannoud N, Dalotto-Moreno T, Kindgard L, et al. Hypoxia supports differentiation of terminally exhausted CD8 T Cells. Front Immunol. 2021; 12:660944.

[76] Chen Y, Zander RA, Wu X, et al. BATF regulates progenitor to cytolytic effector CD8(+) T cell transition during chronic viral infection. Nat Immunol. 2021; 22(8): 996-1007.

[77] Seo H, González-Avalos E, Zhang W, et al. BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells. Nat Immunol. 2021; 22(8): 983-995.

[78] BATF and IRF4 prevent CAR T-cell exhaustion. Cancer Discov. 2021; 11(9): OF9.

[79] Man K, Gabriel SS, Liao Y, et al. Transcription factor IRF4 promotes CD8(+) T cell exhaustion and limits the development of memory-like T cells during chronic infection. Immunity. 2017; 47(6): 1129-1141.e5.

[80] Rutishauser RL, Martins GA, Kalachikov S, et al. Transcriptional repressor Blimp-1 promotes CD8(+) T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity. 2009; 31(2): 296-308.

[81] Shin H, Blackburn SD, Intlekofer AM, et al. A role for the transcriptional repressor Blimp-1 in CD8(+) T cell exhaustion during chronic viral infection. Immunity. 2009; 31(2): 309-320.

[82] Crotty S, Johnston RJ, Schoenberger SP. Effectors and memories: bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat Immunol. 2010; 11(2): 114-120.

[83] Scott-Browne JP, López-Moyado IF, Trifari S, et al. Dynamic changes in chromatin accessibility occur in CD8(+) T cells responding to viral infection. Immunity. 2016; 45(6): 1327-1340.

[84] Battistello E, Hixon KA, Comstock DE, et al. Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion. Mol Cell. 2023; 83(8): 1216-1236.e12.

[85] Yang Y, Li X, Liu F, et al. Immunometabolite L-2-HG promotes epigenetic modification of exhausted T cells and improves antitumor immunity. JCI Insight. 2025; 10(7):e174600.

[86] Chen L, Fischle W, Verdin E, Greene WC. Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science. 2001; 293(5535): 1653-1657.

[87] Liu Z, Li X, Gao Y, et al. Epigenetic reprogramming of Runx3 reinforces CD8 + T-cell function and improves the clinical response to immunotherapy. Mol Cancer. 2023; 22(1): 84.

[88] Ahmad K, Brahma S, Henikoff S. Epigenetic pioneering by SWI/SNF family remodelers. Mol Cell. 2024; 84(2): 194-201.

[89] McDonald B, Chick BY, Ahmed NS, et al. Canonical BAF complex activity shapes the enhancer landscape that licenses CD8(+) T cell effector and memory fates. Immunity. 2023; 56(6): 1303-1319.e5.

[90] Guo A, Huang H, Zhu Z, et al. cBAF complex components and MYC cooperate early in CD8(+) T cell fate. Nature. 2022; 607(7917): 135-141.

[91] Belk JA, Yao W, Ly N, et al. Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence. Cancer Cell. 2022; 40(7): 768-786.e7.

[92] Baxter AE, Huang H, Giles JR, et al. The SWI/SNF chromatin remodeling complexes BAF and PBAF differentially regulate epigenetic transitions in exhausted CD8(+) T cells. Immunity. 2023; 56(6): 1320-1340.e10.

[93] Mazzone R, Zwergel C, Mai A, Valente S. Epi-drugs in combination with immunotherapy: a new avenue to improve anticancer efficacy. Clin Epigenetics. 2017; 9: 59.

[94] Ford BR, Vignali PDA, Rittenhouse NL, et al. Tumor microenvironmental signals reshape chromatin landscapes to limit the functional potential of exhausted T cells. Sci Immunol. 2022; 7(74):eabj9123.

[95] Palazon A, Tyrakis PA, Macias D et al. An HIF-1α/VEGF-A axis in cytotoxic T cells regulates tumor progression. Cancer Cell. 2017; 32(5): 669-683.e5.

[96] Doedens AL, Phan AT, Stradner MH, et al. Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat Immunol. 2013; 14(11): 1173-1182.

[97] Shen H, Ojo OA, Ding H, et al. HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells. Nat Commun. 2024; 15(1): 9394.

[98] Ma S, Zhao Y, Lee WC, 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. 2022; 13(1): 4118.

[99] Tan SN, Hao J, Ge J, et al. Regulatory T cells converted from Th1 cells in tumors suppress cancer immunity via CD39. J Exp Med. 2025; 222(4):e20240445.

[100] Dumauthioz N, Tschumi B, Wenes M, et al. Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity. Cell Mol Immunol. 2021; 18(7): 1761-1771.

[101] Yu L, Wei J, Liu P. Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer. Semin Cancer Biol. 2022; 85: 69-94.

[102] Cheung EC, Vousden KH. The role of ROS in tumour development and progression. Nat Rev Cancer. 2022; 22(5): 280-297.

[103] Liu PS, Wang H, Li X, et al. α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat Immunol. 2017; 18(9): 985-994.

[104] Watson MJ, Vignali PDA, Mullett SJ, et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature. 2021; 591(7851): 645-651.

[105] Xie J, Han X, Zhao C, et al. Phosphotyrosine-dependent interaction between the kinases PKCθ and Zap70 promotes proximal TCR signaling. Sci Signal. 2019; 12(577):eaar3349.

[106] Marasco M, Berteotti A, Weyershaeuser J, et al. Molecular mechanism of SHP2 activation by PD-1 stimulation. Sci Adv. 2020; 6(5):eaay4458.

[107] Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunol. 2008; 180(9): 5771-5777.

[108] Ding P, Ma Z, Fan Y, et al. Emerging role of ubiquitination/deubiquitination modification of PD-1/PD-L1 in cancer immunotherapy. Genes Dis. 2023; 10(3): 848-863.

[109] Kumar J, Kumar R, Kumar Singh A, et al. Deletion of Cbl-b inhibits CD8(+) T-cell exhaustion and promotes CAR T-cell function. J Immunother Cancer. 2021; 9(1):e001688.

[110] Augustin RC, Bao R, Luke JJ. Targeting Cbl-b in cancer immunotherapy. J Immunother Cancer. 2023; 11(2):e006007.

[111] Zhou P, Shi H, Huang H, et al. Single-cell CRISPR screens in vivo map T cell fate regulomes in cancer. Nature. 2023; 624(7990): 154-163.

[112] Kang TG, Lan X, Mi T, et al. Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy. Science. 2024; 386(6718):eadl4492.

[113] Zhao E, Maj T, Kryczek I, et al. Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat Immunol. 2016; 17(1): 95-103.

[114] Cheng J, Xiao Y, Peng T, et al. ETV7 limits the antiviral and antitumor efficacy of CD8(+) T cells by diverting their fate toward exhaustion. Nat Cancer. 2025; 6(2): 338-356.

[115] Neubert EN, DeRogatis JM, Lewis SA, et al. HMGB2 regulates the differentiation and stemness of exhausted CD8(+) T cells during chronic viral infection and cancer. Nat Commun. 2023; 14(1): 5631.

[116] Lan X, Mi T, Alli S, et al. Antitumor progenitor exhausted CD8(+) T cells are sustained by TCR engagement. Nat Immunol. 2024; 25(6): 1046-1058.

[117] Lynn RC, Weber EW, Sotillo E, et al. c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature. 2019; 576(7786): 293-300.

[118] Zhang F, Zhou X, DiSpirito JR, Wang C, Wang Y, Shen H. Epigenetic manipulation restores functions of defective CD8⁺ T cells from chronic viral infection. Mol Ther. 2014; 22(9): 1698-1706.

[119] Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr. 2011; 93(4): 884s-890s.

[120] Qiu J, Villa M, Sanin DE, et al. Acetate promotes T cell effector function during glucose restriction. Cell Rep. 2019; 27(7): 2063-2074.e5.

[121] Ho PC, Bihuniak JD, Macintyre AN, et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell. 2015; 162(6): 1217-1228.

[122] Buck MD, O'Sullivan D, Pearce EL. T cell metabolism drives immunity. J Exp Med. 2015; 212(9): 1345-1360.

[123] Scharping NE, Rivadeneira DB, Menk AV, et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat Immunol. 2021; 22(2): 205-215.

[124] Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol. 2018; 19(2): 121-135.

[125] Li T, Han J, Jia L, Hu X, Chen L, Wang Y. PKM2 coordinates glycolysis with mitochondrial fusion and oxidative phosphorylation. Protein Cell. 2019; 10(8): 583-594.

[126] Huang Y, Si X, Shao M, Teng X, Xiao G, Huang H. Rewiring mitochondrial metabolism to counteract exhaustion of CAR-T cells. J Hematol Oncol. 2022; 15(1): 38.

[127] Wang Y, Ma A, Song NJ, et al. Proteotoxic stress response drives T cell exhaustion and immune evasion. Nature. 2025; 647(8091): 1025-1035.

[128] Zhang Z, Ren C, Xiao R, et al. Palmitoylation of TIM-3 promotes immune exhaustion and restrains antitumor immunity. Sci Immunol. 2024; 9(101):eadp7302.

[129] Humblin E, Korpas I, Lu J, et al. Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1(+) PD-1(+) CD8 T cells. Sci Immunol. 2023; 8(86):eadg0878.

[130] Leone RD, Emens LA. Targeting adenosine for cancer immunotherapy. J Immunother Cancer. 2018; 6(1): 57.

[131] Wang Y, Tong C, Dai H, et al. Low-dose decitabine priming endows CAR T cells with enhanced and persistent antitumour potential via epigenetic reprogramming. Nat Commun. 2021; 12(1): 409.

[132] Knudsen NH, Escobar G, Korell F, et al. In vivo CRISPR screens identify modifiers of CAR T cell function in myeloma. Nature. 2025; 646(8086): 953-962.

RIGHTS & PERMISSIONS

2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.