Sadelain, M., Rivière, I. & Riddell, S. Therapeutic T cell engineering. Nature 545, 423–431 (2017).
Google Scholar
Waldman, A. D., Fritz, J. M. & Lenardo, M. J. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat. Rev. Immunol. 20, 651–668 (2020).
Google Scholar
Kumar, B. V., Connors, T. J. & Farber, D. L. Human T Cell Development, Localization, and Function throughout Life. Immunity 48, 202–213 (2018).
Google Scholar
Baessler, A. & Vignali, D. A. A. T Cell Exhaustion. Annu. Rev. Immunol. 42, 179–206 (2024).
Google Scholar
Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015).
Google Scholar
Liu, Z. et al. Immunosenescence: molecular mechanisms and diseases. Signal Transduct. Target Ther. 8, 200 (2023).
Google Scholar
Mittelbrunn, M. & Kroemer, G. Hallmarks of T cell aging. Nat. Immunol. 22, 687–698 (2021).
Google Scholar
Chen, A. C. Y. et al. The aged tumor microenvironment limits T cell control of cancer. Nat. Immunol. 25, 1033–1045 (2024).
Google Scholar
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.e1510 (2024).
Google Scholar
VanderWalde, A. et al. Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma: a randomized phase 2 trial. Nat. Med. 29, 2278–2285 (2023).
Google Scholar
Tian, Z., Liu, M., Zhang, Y. & Wang, X. Bispecific T cell engagers: an emerging therapy for management of hematologic malignancies. J. Hematol. Oncol. 14, 75 (2021).
Google Scholar
Tas, L., Jedema, I. & Haanen, J. B. A. G. Novel strategies to improve efficacy of treatment with tumor-infiltrating lymphocytes (TILs) for patients with solid cancers. Curr. Opin. Oncol. 35, 107–113 (2023).
Google Scholar
Tsimberidou, A. M. et al. T-cell receptor-based therapy: an innovative therapeutic approach for solid tumors. J. Hematol. Oncol. 14, 102 (2021).
Google Scholar
June, C. H. & Sadelain, M. Chimeric Antigen Receptor Therapy. N. Engl. J. Med. 379, 64–73 (2018).
Google Scholar
Slaets, H. et al. Are immunosenescent T cells really senescent? Aging Cell 23, e14300 (2024).
Google Scholar
Kondo, M., Weissman, I. L. & Akashi, K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91, 661–672 (1997).
Google Scholar
Jensen, C. T. et al. FLT3 ligand and not TSLP is the key regulator of IL-7-independent B-1 and B-2 B lymphopoiesis. Blood 112, 2297–2304 (2008).
Google Scholar
Bosselut, R. A Beginner’s Guide to T Cell Development. Methods Mol. Biol. 2580, 3–24 (2023).
Google Scholar
Mendes-da-Cruz, D. A., Lemos, J. P., Belorio, E. P. & Savino, W. Intrathymic Cell Migration: Implications in Thymocyte Development and T Lymphocyte Repertoire Formation. Adv. Exp. Med. Biol. 1471, 139–175 (2025).
Google Scholar
Allende, M. L. et al. Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. J. Biol. Chem. 279, 52487–52492 (2004).
Google Scholar
León, B. & Lund, F. E. Compartmentalization of dendritic cell and T-cell interactions in the lymph node: Anatomy of T-cell fate decisions. Immunol. Rev. 289, 84–100 (2019).
Google Scholar
Lee, G. R. Molecular Mechanisms of T Helper Cell Differentiation and Functional Specialization. Immune Netw. 23, e4 (2023).
Google Scholar
Fraser, J. H., Rincón, M., McCoy, K. D. & Le Gros, G. CTLA4 ligation attenuates AP-1, NFAT and NF-kappaB activity in activated T cells. Eur. J. Immunol. 29, 838–844 (1999).
Google Scholar
Vahedi, G. et al. STATs shape the active enhancer landscape of T cell populations. Cell 151, 981–993 (2012).
Google Scholar
Courtney, A. H., Lo, W. L. & Weiss, A. TCR Signaling: Mechanisms of Initiation and Propagation. Trends Biochem. Sci. 43, 108–123 (2018).
Google Scholar
Gaud, G., Lesourne, R. & Love, P. E. Regulatory mechanisms in T cell receptor signalling. Nat. Rev. Immunol. 18, 485–497 (2018).
Google Scholar
Pen, J. J. et al. in Immune Activation Response, Ch. 3 (Intech Open, 2014).
Shier, P. et al. Tbt-1, a new T-box transcription factor induced in activated Th1 and CD8+ T cells. Immunogenetics 51, 771–778 (2000).
Google Scholar
Chtanova, T. et al. T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J. Immunol. 173, 68–78 (2004).
Google Scholar
Ivanov, I. I. et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).
Google Scholar
Lai, L. et al. Cytotoxic CD4+ T cells: origin, biological functions, diseases and therapeutic targets. Signal Transduct Target Ther. 11, 85 (2026).
Yao, S. et al. Interferon regulatory factor 4 sustains CD8(+) T cell expansion and effector differentiation. Immunity 39, 833–845 (2013).
Google Scholar
Kurachi, M. et al. The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells. Nat. Immunol. 15, 373–383 (2014).
Google Scholar
Chi, H., Pepper, M. & Thomas, P. G. Principles and therapeutic applications of adaptive immunity. Cell 187, 2052–2078 (2024).
Google Scholar
Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).
Google Scholar
Ma, K. et al. T cell-based cancer immunotherapy: opportunities and challenges. Sci. Bull. 70, 1872–1890 (2025).
Google Scholar
Lam, N., Lee, Y. & Farber, D. L. A guide to adaptive immune memory. Nat. Rev. Immunol. 24, 810–829 (2024).
Google Scholar
Sallusto, F. et al. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).
Google Scholar
Derhovanessian, E. et al. Infection with cytomegalovirus but not herpes simplex virus induces the accumulation of late-differentiated CD4+ and CD8+ T-cells in humans. J. Gen. Virol. 92, 2746–2756 (2011).
Google Scholar
Gordon, C. L. et al. Tissue reservoirs of antiviral T cell immunity in persistent human CMV infection. J. Exp. Med. 214, 651–667 (2017).
Google Scholar
Gattinoni, L. et al. A human memory T cell subset with stem cell-like properties. Nat. Med. 17, 1290–1297 (2011).
Google Scholar
Osum, K. C. & Jenkins, M. K. Toward a general model of CD4+ T cell subset specification and memory cell formation. Immunity 56, 475–484 (2023).
Google Scholar
Soon, M. S., Engel, J. A., Lee, H. J. & Haque, A. Development of circulating CD4+ T cell memory. Immunol. Cell Biol. 97, 617–624 (2019).
Google Scholar
Buchholz, V. R., Schumacher, T. N. & Busch, D. H. T Cell Fate at the Single-Cell Level. Annu. Rev. Immunol. 34, 65–92 (2016).
Google Scholar
Crespo, J. et al. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr. Opin. Immunol. 25, 214–221 (2013).
Google Scholar
ElTanbouly, M. A. & Noelle, R. J. Rethinking peripheral T cell tolerance: checkpoints across a T cell’s journey. Nat. Rev. Immunol. 21, 257–267 (2021).
Google Scholar
Grover, A. et al. Single-cell RNA sequencing reveals molecular and functional platelet bias of aged haematopoietic stem cells. Nat. Commun. 7, 11075 (2016).
Google Scholar
Kowalczyk, M. S. et al. Single-cell RNA-seq reveals changes in cell cycle and differentiation programs upon aging of hematopoietic stem cells. Genome Res. 25, 1860–1872 (2015).
Google Scholar
Akbar, A. N. & Henson, S. M. Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat. Rev. Immunol. 11, 289–295 (2011).
Google Scholar
Nikolich-Žugich, J. The twilight of immunity: emerging concepts in aging of the immune system. Nat. Immunol. 19, 10–19 (2018).
Google Scholar
Simpson, R. J. et al. Senescent T-lymphocytes are mobilised into the peripheral blood compartment in young and older humans after exhaustive exercise. Brain Behav. Immun. 22, 544–551 (2008).
Google Scholar
Chou, J. P. & Effros, R. B. T cell replicative senescence in human aging. Curr. Pharm. Des. 19, 1680–1698 (2013).
Google Scholar
Plunkett, F. J. et al. The loss of telomerase activity in highly differentiated CD8+CD28-CD27- T cells is associated with decreased Akt (Ser473) phosphorylation. J. Immunol. 178, 7710–7719 (2007).
Google Scholar
Wang, B., Han, J., Elisseeff, J. H. & Demaria, M. The senescence-associated secretory phenotype and its physiological and pathological implications. Nat. Rev. Mol. Cell Biol. 25, 958–978 (2024).
Google Scholar
Serrano, M. et al. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997).
Google Scholar
Demaria, M. et al. Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov. 7, 165–176 (2017).
Google Scholar
Wiley, C. D. et al. Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype. Cell Metab. 23, 303–314 (2016).
Google Scholar
Speiser, D. E. et al. T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion? Nat. Rev. Immunol. 14, 768–774 (2014).
Google Scholar
Laphanuwat, P., Gomes, D. C. O. & Akbar, A. N. Senescent T cells: Beneficial and detrimental roles. Immunol. Rev. 316, 160–175 (2023).
Google Scholar
Akbar, A. N. & Fletcher, J. M. Memory T cell homeostasis and senescence during aging. Curr. Opin. Immunol. 17, 480–485 (2005).
Google Scholar
Teteloshvili, N. et al. Involvement of MicroRNAs in the Aging-Related Decline of CD28 Expression by Human T Cells. Front. Immunol. 9, 1400 (2018).
Google Scholar
Brunner, S. et al. Upregulation of miR-24 is associated with a decreased DNA damage response upon etoposide treatment in highly differentiated CD8(+) T cells sensitizing them to apoptotic cell death. Aging Cell 11, 579–587 (2012).
Google Scholar
Lopes-Paciencia, S. et al. The senescence-associated secretory phenotype and its regulation. Cytokine 117, 15–22 (2019).
Google Scholar
Callender, L. A. et al. Mitochondrial mass governs the extent of human T cell senescence. Aging Cell 19, e13067 (2020).
Google Scholar
Rausser, S. et al. Mitochondrial phenotypes in purified human immune cell subtypes and cell mixtures. Elife. 10, e70899 (2021).
Tao, W., Yu, Z. & Han, J. J. Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators. Cell Metab. 36, 1126–1143.e1125 (2024).
Google Scholar
Sallusto, F., Geginat, J. & Lanzavecchia, A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 22, 745–763 (2004).
Google Scholar
Callender, L. A. et al. Human CD8+ EMRA T cells display a senescence-associated secretory phenotype regulated by p38 MAPK. Aging Cell. 17, e12675 (2018).
Henson, S. M. et al. Blockade of PD-1 or p38 MAP kinase signaling enhances senescent human CD8(+) T-cell proliferation by distinct pathways. Eur. J. Immunol. 45, 1441–1451 (2015).
Google Scholar
Brenchley, J. M. et al. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood 101, 2711–2720 (2003).
Google Scholar
Wu, Y. et al. Revitalizing T cells: breakthroughs and challenges in overcoming T cell exhaustion. Signal Transduct. Target Ther. 11, 2 (2026).
Google Scholar
Sen, D. R. et al. The epigenetic landscape of T cell exhaustion. Science 354, 1165–1169 (2016).
Google Scholar
Wherry, E. J. T cell exhaustion. Nat. Immunol. 12, 492–499 (2011).
Google Scholar
Wherry, E. J. et al. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J. Virol. 77, 4911–4927 (2003).
Google Scholar
Utzschneider, D. T. et al. High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival. J. Exp. Med. 213, 1819–1834 (2016).
Google Scholar
Blackburn, S. D., Shin, H., Freeman, G. J. & Wherry, E. J. Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade. Proc. Natl. Acad. Sci. USA 105, 15016–15021 (2008).
Google Scholar
Kallies, A., Zehn, D. & Utzschneider, D. T. Precursor exhausted T cells: key to successful immunotherapy? Nat. Rev. Immunol. 20, 128–136 (2020).
Google Scholar
Zuniga, E. I. & Harker, J. A. T-cell exhaustion due to persistent antigen: quantity not quality? Eur. J. Immunol. 42, 2285–2289 (2012).
Google Scholar
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.e828 (2020).
Google Scholar
Good, C. R. et al. An NK-like CAR T cell transition in CAR T cell dysfunction. Cell 184, 6081–6100.e6026 (2021).
Google Scholar
Daniel, B. et al. Divergent clonal differentiation trajectories of T cell exhaustion. Nat. Immunol. 23, 1614–1627 (2022).
Google Scholar
Khan, O. et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 571, 211–218 (2019).
Google Scholar
Liu, X. et al. Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction. Nature 567, 525–529 (2019).
Google Scholar
Gunasinghe, S. D., Peres, N. G., Goyette, J. & Gaus, K. Biomechanics of T Cell Dysfunctions in Chronic Diseases. Front. Immunol. 12, 600829 (2021).
Google Scholar
Zhao, Y., Shao, Q. & Peng, G. Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment. Cell Mol. Immunol. 17, 27–35 (2020).
Google Scholar
Lanna, A., Henson, S. M., Escors, D. & Akbar, A. N. The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat. Immunol. 15, 965–972 (2014).
Google Scholar
Shive, C. L. et al. Markers of T Cell Exhaustion and Senescence and Their Relationship to Plasma TGF-β Levels in Treated HIV+ Immune Non-responders. Front. Immunol. 12, 638010 (2021).
Google Scholar
Kasakovski, D., Xu, L. & Li, Y. T cell senescence and CAR-T cell exhaustion in hematological malignancies. J. Hematol. Oncol. 11, 91 (2018).
Google Scholar
Chung, D. J. et al. T-cell Exhaustion in Multiple Myeloma Relapse after Autotransplant: Optimal Timing of Immunotherapy. Cancer Immunol. Res. 4, 61–71 (2016).
Google Scholar
Leão, R. et al. Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: clinical impacts in cancer. J. Biomed. Sci. 25, 22 (2018).
Google Scholar
Patrick, M. & Weng, N. P. Expression and regulation of telomerase in human T cell differentiation, activation, aging and diseases. Cell Immunol. 345, 103989 (2019).
Google Scholar
Matthe, D. M. et al. Telomerase deficiency reflects age-associated changes in CD4+ T cells. Immun. Ageing 19, 16 (2022).
Google Scholar
Nguyen, L. N. T. et al. TRF2 inhibition rather than telomerase disruption drives CD4T cell dysfunction during chronic viral infection. J Cell Sci. 135, jcs259481 (2022).
Qian, Y., Yang, L. & Cao, S. Telomeres and telomerase in T cells of tumor immunity. Cell Immunol. 289, 63–69 (2014).
Google Scholar
Lanna, A. et al. An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory. Nat. Cell Biol. 24, 1461–1474 (2022).
Google Scholar
Hodes, R. J., Hathcock, K. S. & Weng, N. P. Telomeres in T and B cells. Nat. Rev. Immunol. 2, 699–706 (2002).
Google Scholar
Zhu, Y. et al. Telomere and its role in the aging pathways: telomere shortening, cell senescence and mitochondria dysfunction. Biogerontology 20, 1–16 (2019).
Google Scholar
Henson, S. M. et al. p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8⁺ T cells. J. Clin. Invest 124, 4004–4016 (2014).
Google Scholar
d’Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003).
Google Scholar
Herbig, U. et al. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol. Cell 14, 501–513 (2004).
Google Scholar
Sahin, E. et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470, 359–365 (2011).
Google Scholar
Janelle, V. et al. p16(INK4a) Regulates Cellular Senescence in PD-1-Expressing Human T Cells. Front. Immunol. 12, 698565 (2021).
Google Scholar
Rincón, M. MAP-kinase signaling pathways in T cells. Curr. Opin. Immunol. 13, 339–345 (2001).
Google Scholar
Fülöp, T. et al. Age-related impairment of p56lck and ZAP-70 activities in human T lymphocytes activated through the TcR/CD3 complex. Exp. Gerontol. 34, 197–216 (1999).
Google Scholar
Lanna, A. et al. A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging. Nat. Immunol. 18, 354–363 (2017).
Google Scholar
Raychaudhuri, K. et al. CD28 shapes T cell receptor signaling by regulating Lck dynamics and ZAP70 activation. Front. Immunol. 15, 1503018 (2024).
Google Scholar
Pereira, B. I. et al. Sestrins induce natural killer function in senescent-like CD8(+) T cells. Nat. Immunol. 21, 684–694 (2020).
Google Scholar
Zöphel, D. et al. Faster cytotoxicity with age: Increased perforin and granzyme levels in cytotoxic CD8+ boost cancer cell elimination. Aging Cell 21, e13668 (2022).
Google Scholar
Dahlquist, K. J. V. et al. In vivo labeling reveals that degranulation is increased under supraphysiological TCR stimulation, but not infection, in CD8+ T cells from old mice. Geroscience 48, 897–913 (2025).
Zöphel, D. et al. Heterozygous OT-I mice reveal that antigen-specific CD8+ T cells shift from apoptotic to necrotic killers in the elderly. Aging Cell 22, e13824 (2023).
Google Scholar
Raz, Y. et al. Activation-Induced Autophagy Is Preserved in CD4+ T-Cells in Familial Longevity. J. Gerontol. A Biol. Sci. Med. Sci. 72, 1201–1206 (2017).
Google Scholar
Reynolds, C. A. et al. Restoration of LAMP2A expression in old mice leads to changes in the T cell compartment that support improved immune function. Proc. Natl. Acad. Sci. USA 121, e2322929121 (2024).
Google Scholar
Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. USA 92, 9363–9367 (1995).
Google Scholar
Lee, B. Y. et al. Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell 5, 187–195 (2006).
Google Scholar
Turano, P. S. et al. Epigenetic mechanisms regulating CD8+ T cell senescence in aging humans. bioRxiv https://www.biorxiv.org/content/10.1101/2025.01.17.633634v1.full (2025).
Taylor, R. C. & Dillin, A. Aging as an event of proteostasis collapse. Cold Spring Harb. Perspect. Biol. 3, a004440 (2011).
Chen, Y., Gorelik, G. J., Strickland, F. M. & Richardson, B. C. Decreased ERK and JNK signaling contribute to gene overexpression in “senescent” CD4+CD28- T cells through epigenetic mechanisms. J. Leukoc. Biol. 87, 137–145 (2010).
Google Scholar
Liu, Y., Kuick, R., Hanash, S. & Richardson, B. DNA methylation inhibition increases T cell KIR expression through effects on both promoter methylation and transcription factors. Clin. Immunol. 130, 213–224 (2009).
Google Scholar
Weng, N. P., Akbar, A. N. & Goronzy, J. CD28(-) T cells: their role in the age-associated decline of immune function. Trends Immunol. 30, 306–312 (2009).
Google Scholar
Li, Y., Liu, Y., Strickland, F. M. & Richardson, B. Age-dependent decreases in DNA methyltransferase levels and low transmethylation micronutrient levels synergize to promote overexpression of genes implicated in autoimmunity and acute coronary syndromes. Exp. Gerontol. 45, 312–322 (2010).
Google Scholar
Coppé, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008).
Google Scholar
Hakim, F. T., Flomerfelt, F. A., Boyiadzis, M. & Gress, R. E. Aging, immunity and cancer. Curr. Opin. Immunol. 16, 151–156 (2004).
Google Scholar
Goronzy, J. J. & Weyand, C. M. Mechanisms underlying T cell ageing. Nat. Rev. Immunol. 19, 573–583 (2019).
Google Scholar
Homann, L. et al. IFN-γ and TNF Induce Senescence and a Distinct Senescence-Associated Secretory Phenotype in Melanoma. Cells. 11, 1514 (2022).
González-Osuna, L. et al. p38 mitogen-activated protein kinase drives senescence in CD4+ T lymphocytes and increases their pathological potential. Immun. Ageing 22, 30 (2025).
Google Scholar
Macian, F. Autophagy in T Cell Function and Aging. Front. Cell Dev. Biol. 7, 213 (2019).
Google Scholar
Desdín-Micó, G. et al. T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science 368, 1371–1376 (2020).
Google Scholar
Li, Y. et al. The DNA Repair Nuclease MRE11A Functions as a Mitochondrial Protector and Prevents T Cell Pyroptosis and Tissue Inflammation. Cell Metab. 30, 477–492.e476 (2019).
Google Scholar
Ishikawa, H. & Barber, G. N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008).
Google Scholar
Ishikawa, H., Ma, Z. & Barber, G. N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792 (2009).
Google Scholar
Han, X. et al. Autolysosomal degradation of cytosolic chromatin fragments antagonizes oxidative stress-induced senescence. J. Biol. Chem. 295, 4451–4463 (2020).
Google Scholar
Qi, X. et al. Curcumol Suppresses CCF-Mediated Hepatocyte Senescence Through Blocking LC3B-Lamin B1 Interaction in Alcoholic Fatty Liver Disease. Front. Pharm. 13, 912825 (2022).
Google Scholar
Daniels, M. A. & Teixeiro, E. The NF-κB signaling network in the life of T cells. Front. Immunol. 16, 1559494 (2025).
Google Scholar
Gupta, S. et al. Role of NF-kappaB signaling pathway in increased tumor necrosis factor-alpha-induced apoptosis of lymphocytes in aged humans. Cell Death Differ. 12, 177–183 (2005).
Google Scholar
Gupta, S., Su, H., Bi, R. & Gollapudi, S. Differential sensitivity of naïve and memory subsets of human CD8+ T cells to TNF-alpha-induced apoptosis. J. Clin. Immunol. 26, 193–203 (2006).
Google Scholar
Spaulding, C., Guo, W. & Effros, R. B. Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp. Gerontol. 34, 633–644 (1999).
Google Scholar
Schirmer, M., Vallejo, A. N., Weyand, C. M. & Goronzy, J. J. Resistance to apoptosis and elevated expression of Bcl-2 in clonally expanded CD4+CD28- T cells from rheumatoid arthritis patients. J. Immunol. 161, 1018–1025 (1998).
Google Scholar
Vallejo, A. N., Schirmer, M., Weyand, C. M. & Goronzy, J. J. Clonality and longevity of CD4+CD28null T cells are associated with defects in apoptotic pathways. J. Immunol. 165, 6301–6307 (2000).
Google Scholar
Kovalcsik, E. et al. Proteasome-mediated reduction in proapoptotic molecule Bim renders CD4⁺CD28null T cells resistant to apoptosis in acute coronary syndrome. Circulation 131, 709–720 (2015).
Google Scholar
Gupta, S. et al. A paradox of immunodeficiency and inflammation in human aging: lessons learned from apoptosis. Immun. Ageing 3, 5 (2006).
Google Scholar
Pyaram, K., Sen, J. M. & Chang, C. H. Temporal regulation of Wnt/β-catenin signaling is important for invariant NKT cell development and terminal maturation. Mol. Immunol. 85, 47–56 (2017).
Google Scholar
Jeannet, G. et al. Essential role of the Wnt pathway effector Tcf-1 for the establishment of functional CD8 T cell memory. Proc. Natl. Acad. Sci. USA 107, 9777–9782 (2010).
Google Scholar
Yu, Q., Sharma, A. & Sen, J. M. TCF1 and beta-catenin regulate T cell development and function. Immunol. Res. 47, 45–55 (2010).
Google Scholar
Staal, F. J., Luis, T. C. & Tiemessen, M. M. WNT signalling in the immune system: WNT is spreading its wings. Nat. Rev. Immunol. 8, 581–593 (2008).
Google Scholar
Kared, H. et al. Immunological history governs human stem cell memory CD4 heterogeneity via the Wnt signaling pathway. Nat. Commun. 11, 821 (2020).
Google Scholar
Tserel, L. et al. Age-related profiling of DNA methylation in CD8+ T cells reveals changes in immune response and transcriptional regulator genes. Sci. Rep. 5, 13107 (2015).
Google Scholar
Sturmlechner, I. et al. T cell fate decisions during memory cell generation with aging. Semin. Immunol. 69, 101800 (2023).
Google Scholar
Delpoux, A. et al. FOXO1 constrains activation and regulates senescence in CD8 T cells. Cell Rep. 34, 108674 (2021).
Google Scholar
Varecza, Z. et al. Multiple suppression pathways of canonical Wnt signalling control thymic epithelial senescence. Mech. Ageing Dev. 132, 249–256 (2011).
Google Scholar
Ferrando-Martínez, S. et al. WNT signaling suppression in the senescent human thymus. J. Gerontol. A Biol. Sci. Med. Sci. 70, 273–281 (2015).
Google Scholar
Griffith, A. V. et al. Metabolic Damage and Premature Thymus Aging Caused by Stromal Catalase Deficiency. Cell Rep. 12, 1071–1079 (2015).
Google Scholar
Marcovecchio, G. E. et al. Premature Senescence and Increased Oxidative Stress in the Thymus of Down Syndrome Patients. Front. Immunol. 12, 669893 (2021).
Google Scholar
Rode, I. et al. Foxn1 Protein Expression in the Developing, Aging, and Regenerating Thymus. J. Immunol. 195, 5678–5687 (2015).
Google Scholar
Reis, M. D. et al. Decline of FOXN1 gene expression in human thymus correlates with age: possible epigenetic regulation. Immun. Ageing 12, 18 (2015).
Google Scholar
Panwar, V. et al. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal Transduct. Target Ther. 8, 375 (2023).
Google Scholar
Cayo, A. et al. mTOR Activity and Autophagy in Senescent Cells, a Complex Partnership. Int J Mol Sci. 22, 8149 (2021).
Liu, L. et al. Metabolic reprogramming in T cell senescence: a novel strategy for cancer immunotherapy. Cell Death Discov. 11, 161 (2025).
Google Scholar
Hukelmann, J. L. et al. The cytotoxic T cell proteome and its shaping by the kinase mTOR. Nat. Immunol. 17, 104–112 (2016).
Google Scholar
Drouet, M. et al. Age-associated changes in mitochondrial parameters on peripheral human lymphocytes. Exp. Gerontol. 34, 843–852 (1999).
Google Scholar
Kawakami, S., Johmura, Y. & Nakanishi, M. Intracellular acidification and glycolysis modulate inflammatory pathway in senescent cells. J. Biochem 176, 97–108 (2024).
Google Scholar
Egorov, E. S. et al. The Changing Landscape of Naive T Cell Receptor Repertoire With Human Aging. Front. Immunol. 9, 1618 (2018).
Google Scholar
Sun, X. et al. Longitudinal analysis reveals age-related changes in the T cell receptor repertoire of human T cell subsets. J. Clin. Invest. 132, e158122 (2022).
Kallemeijn, M. J. et al. Next-Generation Sequencing Analysis of the Human TCRγδ+ T-Cell Repertoire Reveals Shifts in Vγ- and Vδ-Usage in Memory Populations upon Aging. Front. Immunol. 9, 448 (2018).
Google Scholar
Rudd, B. D., Venturi, V., Davenport, M. P. & Nikolich-Zugich, J. Evolution of the antigen-specific CD8+ TCR repertoire across the life span: evidence for clonal homogenization of the old TCR repertoire. J. Immunol. 186, 2056–2064 (2011).
Google Scholar
Fortelny, N. et al. JAK-STAT signaling maintains homeostasis in T cells and macrophages. Nat. Immunol. 25, 847–859 (2024).
Google Scholar
Toma, G. et al. Transcriptional Analysis of Total CD8+ T cells and CD8+CD45RA- memory T cells from young and old healthy blood donors. Front. Immunol. 13, 806906 (2022).
Google Scholar
Ma, F. et al. Tumor extracellular vesicle-derived PD-L1 promotes T cell senescence through lipid metabolism reprogramming. Sci. Transl. Med. 17, eadm7269 (2025).
Google Scholar
Singh, A. K., Althoff, M. J. & Cancelas, J. A. Signaling Pathways Regulating Hematopoietic Stem Cell and Progenitor Aging. Curr. Stem Cell Rep. 4, 166–181 (2018).
Google Scholar
Zukowski, E. et al. STAT3 modulates CD4+ T mitochondrial dynamics and function in aging. Aging Cell 22, e13996 (2023).
Google Scholar
Liu, X. et al. Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition. Nat. Commun. 9, 249 (2018).
Google Scholar
Seki, Y. et al. IL-7/STAT5 cytokine signaling pathway is essential but insufficient for maintenance of naive CD4 T cell survival in peripheral lymphoid organs. J. Immunol. 178, 262–270 (2007).
Google Scholar
Arango-Franco, C. A. et al. IL-7-dependent and -independent lineages of IL-7R-dependent human T cells. J. Clin. Invest. 134, 3370–81 (2024).
Morandi, F., Horenstein, A. L. & Malavasi, F. The Key Role of NAD+ in Anti-Tumor Immune Response: An Update. Front. Immunol. 12, 658263 (2021).
Google Scholar
Gibson, B. A. & Kraus, W. L. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat. Rev. Mol. Cell Biol. 13, 411–424 (2012).
Google Scholar
Gomes, A. P. et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624–1638 (2013).
Google Scholar
Fang, E. F. et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell 157, 882–896 (2014).
Google Scholar
Hope, H. C. et al. Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure. Nat Cancer 6, 1524–1536 (2025).
Lv, L. L. et al. High CD38 expression defines a mitochondrial function-adapted CD8+ T cell subset with implications for lung cancer immunotherapy. Cancer Immunol. Immunother. 74, 49 (2025).
Google Scholar
Guo, Z. et al. DCAF1 regulates Treg senescence via the ROS axis during immunological aging. J. Clin. Invest. 130, 5893–5908 (2020).
Google Scholar
Kim, C. et al. Histone deficiency and accelerated replication stress in T cell aging. J. Clin. Invest. 131, e143632 (2021).
Ye, Z. et al. Regulation of miR-181a expression in T cell aging. Nat. Commun. 9, 3060 (2018).
Google Scholar
Martinez, G. J. et al. The transcription factor NFAT promotes exhaustion of activated CD8⁺ T cells. Immunity 42, 265–278 (2015).
Google Scholar
Seo, H. et al. BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells. Nat. Immunol. 22, 983–995 (2021).
Google Scholar
Scott, A. C. et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571, 270–274 (2019).
Google Scholar
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).
Google Scholar
Chen, J. et al. NR4A transcription factors limit CAR T cell function in solid tumours. Nature 567, 530–534 (2019).
Google Scholar
Redd, P. S. et al. H3K4me3 mediates the NF-κB p50 homodimer binding to the pdcd1 promoter to activate PD-1 transcription in T cells. Oncoimmunology 7, e1483302 (2018).
Google Scholar
Li, P. et al. BATF-JUN is critical for IRF4-mediated transcription in T cells. Nature 490, 543–546 (2012).
Google Scholar
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.e1125 (2017).
Google Scholar
Sun, Q. et al. STAT3 regulates CD8+ T cell differentiation and functions in cancer and acute infection. J. Exp. Med. 220, e20220686 (2023).
Ravi, V. M. et al. T-cell dysfunction in the glioblastoma microenvironment is mediated by myeloid cells releasing interleukin-10. Nat. Commun. 13, 925 (2022).
Google Scholar
Huang, L. et al. T-cell Senescence in the Tumor Microenvironment. Cancer Immunol. Res. 13, 618–632 (2025).
Google Scholar
Bregni, M., Badoglio, M., Pedrazzoli, P. & Lanza, F. Is allogeneic transplant for solid tumors still alive? Bone Marrow Transpl. 51, 751–752 (2016).
Google Scholar
Leko, V. & Rosenberg, S. A. Identifying and Targeting Human Tumor Antigens for T Cell-Based Immunotherapy of Solid Tumors. Cancer Cell 38, 454–472 (2020).
Google Scholar
Chemnitz, J. M. et al. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J. Immunol. 173, 945–954 (2004).
Google Scholar
Hui, E. et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355, 1428–1433 (2017).
Google Scholar
Schadendorf, D. et al. Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J. Clin. Oncol. 33, 1889–1894 (2015).
Google Scholar
Postow, M. A. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372, 2006–2017 (2015).
Google Scholar
Motzer, R. J. et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).
Google Scholar
Brahmer, J. et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N. Engl. J. Med. 373, 123–135 (2015).
Google Scholar
Abou-Alfa, G. K. et al. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 1, EVIDoa2100070 (2022).
Google Scholar
Powles, T. et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N. Engl. J. Med. 383, 1218–1230 (2020).
Google Scholar
Makharadze, T. et al. Cemiplimab Plus Chemotherapy Versus Chemotherapy Alone in Advanced NSCLC: 2-Year Follow-Up From the Phase 3 EMPOWER-Lung 3 Part 2 Trial. J. Thorac. Oncol. 18, 755–768 (2023).
Google Scholar
Mirza, M. R. et al. Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. N. Engl. J. Med. 388, 2145–2158 (2023).
Google Scholar
Mimura, K. et al. PD-L1 expression is mainly regulated by interferon gamma associated with JAK-STAT pathway in gastric cancer. Cancer Sci. 109, 43–53 (2018).
Google Scholar
Ayers, M. et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Invest 127, 2930–2940 (2017).
Google Scholar
Ikemizu, S. et al. Structure and dimerization of a soluble form of B7-1. Immunity 12, 51–60 (2000).
Google Scholar
Tai, X. et al. Basis of CTLA-4 function in regulatory and conventional CD4(+) T cells. Blood 119, 5155–5163 (2012).
Google Scholar
Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 20, 1370–1385 (2019).
Google Scholar
Hellmann, M. D. et al. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N. Engl. J. Med. 381, 2020–2031 (2019).
Google Scholar
Wolchok, J. D. et al. Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma. N. Engl. J. Med. 392, 11–22 (2025).
Google Scholar
Cascone, T. et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nat. Med. 27, 504–514 (2021).
Google Scholar
Wu, K. et al. The efficacy and safety of combination of PD-1 and CTLA-4 inhibitors: a meta-analysis. Exp. Hematol. Oncol. 8, 26 (2019).
Google Scholar
Wei, S. C. et al. Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies. Proc. Natl. Acad. Sci. USA 116, 22699–22709 (2019).
Google Scholar
Wang, D. Y. et al. Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. JAMA Oncol. 4, 1721–1728 (2018).
Google Scholar
De Velasco, G. et al. Comprehensive Meta-analysis of Key Immune-Related Adverse Events from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients. Cancer Immunol. Res. 5, 312–318 (2017).
Google Scholar
Yu, Y. et al. T Cell Exhaustion in Cancer Immunotherapy: Heterogeneity, Mechanisms, and Therapeutic Opportunities. Adv. Sci. 13, e20634, (2026).
Sidaway, P. Tiragolumab active in PD-L1+ NSCLC. Nat. Rev. Clin. Oncol. 19, 428 (2022).
Google Scholar
Guan, X. et al. Anti-TIGIT antibody improves PD-L1 blockade through myeloid and Treg cells. Nature 627, 646–655 (2024).
Google Scholar
Tawbi, H. A. et al. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N. Engl. J. Med. 386, 24–34 (2022).
Google Scholar
Andrews, L. P. et al. LAG-3 and PD-1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN-gamma dependent anti-tumor immunity. Cell 187, 4355–4372.e4322 (2024).
Google Scholar
Cai, L., Li, Y., Tan, J. & Xu, L. Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy. J. Hematol. Oncol. 16, 101 (2023).
Google Scholar
Maleki Vareki, S. High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors. J. Immunother. Cancer 6, 157 (2018).
Google Scholar
Barnett, R. M. et al. Blood-based tumor mutational burden impacts clinical outcomes of immune checkpoint inhibitor treated breast and prostate cancers. Commun. Med. 4, 256 (2024).
Google Scholar
Pulte, E. D. et al. FDA Supplemental Approval: Blinatumomab for Treatment of Relapsed and Refractory Precursor B-Cell Acute Lymphoblastic Leukemia. Oncologist 23, 1366–1371 (2018).
Google Scholar
Mohan, M. et al. Teclistamab in relapsed refractory multiple myeloma: multi-institutional real-world study. Blood Cancer J. 14, 35 (2024).
Google Scholar
Cohen, Y. C. et al. Talquetamab plus Teclistamab in Relapsed or Refractory Multiple Myeloma. N. Engl. J. Med. 392, 138–149 (2025).
Google Scholar
Lesokhin, A. M. et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat. Med. 29, 2259–2267 (2023).
Google Scholar
Bumma, N. et al. Linvoseltamab for Treatment of Relapsed/Refractory Multiple Myeloma. J. Clin. Oncol. 42, 2702–2712 (2024).
Google Scholar
Budde, L. E. et al. Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. Lancet Oncol. 23, 1055–1065 (2022).
Google Scholar
Thieblemont, C. et al. Epcoritamab in relapsed/refractory large B-cell lymphoma: 2-year follow-up from the pivotal EPCORE NHL-1 trial. Leukemia 38, 2653–2662 (2024).
Google Scholar
Kim, W. S. et al. Odronextamab monotherapy in patients with relapsed/refractory diffuse large B cell lymphoma: primary efficacy and safety analysis in phase 2 ELM-2 trial. Nat. Cancer 6, 528–539 (2025).
Google Scholar
Liu, Y. et al. FDA Approval Summary: Tarlatamab for the Treatment of Extensive Stage Small Cell Lung Cancer. Clin. Cancer Res. 32, 1191–1195 (2026).
Middleton, M. R. et al. Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma. Clin. Cancer Res. 26, 5869–5878 (2020).
Google Scholar
Staflin, K. et al. Target arm affinities determine preclinical efficacy and safety of anti-HER2/CD3 bispecific antibody. JCI Insight. 5, e133757 (2020).
Dickinson, M. J. et al. Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N. Engl. J. Med. 387, 2220–2231 (2022).
Google Scholar
Bar, N. et al. Alnuctamab, a bivalent B-cell maturation antigen-targeting T cell engager for patients with relapsed or refractory multiple myeloma: results from a phase 1, first-in-human study. Leukemia 40, 481–490 (2026).
Google Scholar
Carretero-Iglesia, L. et al. ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells. Nat. Cancer 5, 1494–1514 (2024).
Google Scholar
Zhao, L. et al. A novel CD19/CD22/CD3 trispecific antibody enhances therapeutic efficacy and overcomes immune escape against B-ALL. Blood 140, 1790–1802 (2022).
Google Scholar
Patel, K. K. et al. From concept to cure: The evolution of CAR-T cell therapy. Mol. Ther. 33, 2123–2140 (2025).
Google Scholar
Chesney, J. et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. J Immunother Cancer. 10, e005755 (2022).
Mony, U. & Veeraraghavan, V. P. Outcomes of tumor-infiltrating lymphocyte therapy in solid tumours – A systematic review and meta analysis. Crit. Rev. Oncol. Hematol. 209, 104671 (2025).
Google Scholar
Cohen, C. J. et al. Enhanced antitumor activity of murine-human hybrid T-cell receptor (TCR) in human lymphocytes is associated with improved pairing and TCR/CD3 stability. Cancer Res. 66, 8878–8886 (2006).
Google Scholar
Bialer, G. et al. Selected murine residues endow human TCR with enhanced tumor recognition. J. Immunol. 184, 6232–6241 (2010).
Google Scholar
Cohen, C. J. et al. Enhanced antitumor activity of T cells engineered to express T-cell receptors with a second disulfide bond. Cancer Res. 67, 3898–3903 (2007).
Google Scholar
Kuball, J. et al. Facilitating matched pairing and expression of TCR chains introduced into human T cells. Blood 109, 2331–2338 (2007).
Google Scholar
Li, D. et al. Genetically engineered T cells for cancer immunotherapy. Signal Transduct. Target Ther. 4, 35 (2019).
Google Scholar
Barnett, K. K. et al. FDA Approval Summary: Afamitresgene Autoleucel for Adults with HLA-Restricted, MAGE-A4-Positive Unresectable or Metastatic Synovial Sarcoma after Prior Chemotherapy. Clin. Cancer Res. 31, 3112–3117 (2025).
Google Scholar
Hatipoglu, E., Furness, A. J. S. & Jones, R. L. Letetresgene Autoleucel: A Milestone in Treatment of Myxoid/Round Cell Liposarcoma. J. Clin. Oncol. 43, 1755–1757 (2025).
Google Scholar
Yang, M., Zhong, P., Jiao, H. & Wei, P. Features of HLA-A*02 in Identifying Eligible Patients for Tecelra TCR-T Therapy. Cancer Sci. 116, 2320–2322 (2025).
Google Scholar
van Loenen, M. M. et al. Mixed T cell receptor dimers harbor potentially harmful neoreactivity. Proc. Natl. Acad. Sci. USA 107, 10972–10977 (2010).
Google Scholar
Bendle, G. M. et al. Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy. Nat. Med. 16, 565–570 (2010).
Google Scholar
Rosenberg, S. A. Of mice, not men: no evidence for graft-versus-host disease in humans receiving T-cell receptor-transduced autologous T cells. Mol. Ther. 18, 1744–1745 (2010).
Google Scholar
Hanssens, H. et al. The antigen-binding moiety in the driver’s seat of CARs. Med Res Rev. 42, 306–342 (2022).
Google Scholar
Roddie, C. et al. Obecabtagene Autoleucel in Adults with B-Cell Acute Lymphoblastic Leukemia. N. Engl. J. Med. 391, 2219–2230 (2024).
Google Scholar
Cappell, K. M. & Kochenderfer, J. N. Long-term outcomes following CAR T cell therapy: what we know so far. Nat. Rev. Clin. Oncol. 20, 359–371 (2023).
Google Scholar
Berdeja, J. G. et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet 398, 314–324 (2021).
Google Scholar
Eshhar, Z., Waks, T., Gross, G. & Schindler, D. G. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc. Natl. Acad. Sci. USA 90, 720–724 (1993).
Google Scholar
Firor, A. E., Jares, A. & Ma, Y. From humble beginnings to success in the clinic: Chimeric antigen receptor-modified T-cells and implications for immunotherapy. Exp. Biol. Med. 240, 1087–1098 (2015).
Google Scholar
June, C. H., Ledbetter, J. A., Linsley, P. S. & Thompson, C. B. Role of the CD28 receptor in T-cell activation. Immunol. Today 11, 211–216 (1990).
Google Scholar
Krause, A. et al. Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. J. Exp. Med. 188, 619–626 (1998).
Google Scholar
Goodman, D. B. et al. Pooled screening of CAR T cells identifies diverse immune signaling domains for next-generation immunotherapies. Sci. Transl. Med. 14, eabm1463 (2022).
Google Scholar
Mikolič, V. et al. Toll-like receptor 4 signaling activation domains promote CAR T cell function against solid tumors. Mol. Ther. Oncol. 32, 200815 (2024).
Google Scholar
Tan, J. et al. Chimeric antigen receptors containing the OX40 signalling domain enhance the persistence of T cells even under repeated stimulation with multiple myeloma target cells. J. Hematol. Oncol. 15, 39 (2022).
Google Scholar
Uslu, U. & June, C. H. Beyond the blood: expanding CAR T cell therapy to solid tumors. Nat. Biotechnol. 43, 506–515 (2025).
Google Scholar
Carpenter, R. O. et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin. Cancer Res. 19, 2048–2060 (2013).
Google Scholar
Mullard, A. FDA approves fourth CAR-T cell therapy. Nat. Rev. Drug Discov. 20, 166 (2021).
Google Scholar
Fowler, N. H. et al. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat. Med. 28, 325–332 (2022).
Google Scholar
Maude, S. L. et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N. Engl. J. Med. 378, 439–448 (2018).
Google Scholar
Neelapu, S. S. et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017).
Google Scholar
Shah, B. D. et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet 398, 491–502 (2021).
Google Scholar
Abramson, J. S. et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet 396, 839–852 (2020).
Google Scholar
Munshi, N. C. et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N. Engl. J. Med. 384, 705–716 (2021).
Google Scholar
Jacobson, C. A. et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 23, 91–103 (2022).
Google Scholar
Wang, M. et al. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N. Engl. J. Med. 382, 1331–1342 (2020).
Google Scholar
Locke, F. L. et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 20, 31–42 (2019).
Google Scholar
Martin, T. et al. Ciltacabtagene Autoleucel, an Anti-B-cell Maturation Antigen Chimeric Antigen Receptor T-Cell Therapy, for Relapsed/Refractory Multiple Myeloma: CARTITUDE-1 2-Year Follow-Up. J. Clin. Oncol. 41, 1265–1274 (2023).
Google Scholar
Gauthier, J. et al. Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B-cell malignancies. Blood 137, 323–335 (2021).
Google Scholar
Shah, N. N. et al. Long-Term Follow-Up of CD19-CAR T-Cell Therapy in Children and Young Adults With B-ALL. J. Clin. Oncol. 39, 1650–1659 (2021).
Google Scholar
Chong, E. A., Ruella, M., Schuster, S. J. & Lymphoma Program Investigators at the University of Pennsylvania. Five-Year Outcomes for Refractory B-Cell Lymphomas with CAR T-Cell Therapy. N Engl J Med. 384, 673–674 (2021).
Zhao, W. H. et al. Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: a phase 1, single-arm, open-label, multicenter study in China (LEGEND-2). J. Hematol. Oncol. 15, 86 (2022).
Google Scholar
Baker, D. J. et al. CAR T therapy beyond cancer: the evolution of a living drug. Nature 619, 707–715 (2023).
Google Scholar
Brown, C. E. et al. Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. N. Engl. J. Med. 375, 2561–2569 (2016).
Google Scholar
Majzner, R. G. et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022).
Google Scholar
Qi, C. et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat. Med. 28, 1189–1198 (2022).
Google Scholar
Del Bufalo, F. et al. GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma. N. Engl. J. Med. 388, 1284–1295 (2023).
Google Scholar
Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016).
Google Scholar
Ghoneim, H. E. et al. De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation. Cell 170, 142–157.e119 (2017).
Google Scholar
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).
Google Scholar
Yang, M. Q. et al. Targeting mitochondria: restoring the antitumor efficacy of exhausted T cells. Mol. Cancer 23, 260 (2024).
Google Scholar
Patsoukis, N. et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat. Commun. 6, 6692 (2015).
Google Scholar
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).
Dammeijer, F. et al. The PD-1/PD-L1-Checkpoint Restrains T cell Immunity in Tumor-Draining Lymph Nodes. Cancer Cell 38, 685–700.e688 (2020).
Google Scholar
Liu, X. et al. Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy. J. Immunother Cancer. 10, e005020 (2022).
Kim, K. H. et al. PD-1 blockade-unresponsive human tumor-infiltrating CD8(+) T cells are marked by loss of CD28 expression and rescued by IL-15. Cell Mol. Immunol. 18, 385–397 (2021).
Google Scholar
Sun, W. et al. CD57-positive CD8 + T cells define the response to anti-programmed cell death protein-1 immunotherapy in patients with advanced non-small cell lung cancer. NPJ Precis. Oncol. 8, 25 (2024).
Google Scholar
Philipp, N. et al. T-cell exhaustion induced by continuous bispecific molecule exposure is ameliorated by treatment-free intervals. Blood 140, 1104–1118 (2022).
Google Scholar
Haber, L. et al. Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning. Sci. Rep. 11, 14397 (2021).
Google Scholar
Poussin, M. et al. Dichotomous impact of affinity on the function of T cell engaging bispecific antibodies. J. Immunother Cancer. 9, e002444 (2021).
Leithner, A. et al. Solution structure and synaptic analyses reveal determinants of bispecific T cell engager potency. Proc. Natl. Acad. Sci. USA 122, e2425781122 (2025).
Google Scholar
Dickopf, S., Georges, G. J. & Brinkmann, U. Format and geometries matter: Structure-based design defines the functionality of bispecific antibodies. Comput Struct. Biotechnol. J. 18, 1221–1227 (2020).
Google Scholar
Zhang, Y. et al. Geometric Antibody Engineering Reveals the Spatial Factor on the Efficacy of Bispecific T Cell Engagers. ACS Chem. Biol. 19, 916–925 (2024).
Google Scholar
Wu, D. et al. Optimization of a Novel 2 + 2 BCMA × CD3 Bispecific Antibody for Minimized Cytokine Release and Potent Efficacy. Mol. Cancer Ther. 24, 1600–1610 (2025).
Google Scholar
Albayrak, G., Wan, P. K., Fisher, K. & Seymour, L. W. T cell engagers: expanding horizons in oncology and beyond. Br. J. Cancer 133, 1241–1249 (2025).
Google Scholar
Friedrich, M. J. et al. The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients. Cancer Cell 41, 711–725.e716 (2023).
Google Scholar
Casey, M. et al. Regulatory T cells hamper the efficacy of T-cell-engaging bispecific antibody therapy. Haematologica 109, 787–798 (2024).
Google Scholar
Zelle-Rieser, C. et al. T cells in multiple myeloma display features of exhaustion and senescence at the tumor site. J. Hematol. Oncol. 9, 116 (2016).
Google Scholar
Wang, J. et al. Drug-loaded bispecific T cell nanoengager overcomes T cell exhaustion for potent cancer immunotherapy. Proc. Natl. Acad. Sci. USA 122, e2409564122 (2025).
Google Scholar
Ayala Ceja, M. et al. CAR-T cell manufacturing: Major process parameters and next-generation strategies. J. Exp. Med. 221, e20230903 (2024).
Fraietta, J. A. et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat. Med. 24, 563–571 (2018).
Google Scholar
Fagnoni, F. F. et al. Expansion of cytotoxic CD8+ CD28- T cells in healthy ageing people, including centenarians. Immunology 88, 501–507 (1996).
Google Scholar
Suen, H. et al. Multiple myeloma causes clonal T-cell immunosenescence: identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade. Leukemia 30, 1716–1724 (2016).
Google Scholar
Das, R. K., Vernau, L., Grupp, S. A. & Barrett, D. M. Naïve T-cell Deficits at Diagnosis and after Chemotherapy Impair Cell Therapy Potential in Pediatric Cancers. Cancer Discov. 9, 492–499 (2019).
Google Scholar
Iacoboni, G. et al. Recent Bendamustine Treatment Before Apheresis Has a Negative Impact on Outcomes in Patients With Large B-Cell Lymphoma Receiving Chimeric Antigen Receptor T-Cell Therapy. J. Clin. Oncol. 42, 205–217 (2024).
Google Scholar
Nowicki, T. S. et al. Characterization of Postinfusion Phenotypic Differences in Fresh Versus Cryopreserved TCR Engineered Adoptive Cell Therapy Products. J. Immunother. 41, 248–259 (2018).
Google Scholar
Guha, P. et al. Frontline Science: Functionally impaired geriatric CAR-T cells rescued by increased α5β1 integrin expression. J. Leukoc. Biol. 102, 201–208 (2017).
Google Scholar
Rutella, S. et al. Immune dysfunction signatures predict outcomes and define checkpoint blockade-unresponsive microenvironments in acute myeloid leukemia. J. Clin. Invest. 132, e159579 (2022).
Dreyzin, A. et al. Immunophenotype of CAR T cells and apheresis products predicts response in CD22 CAR T cell trial for B cell acute lymphoblastic leukemia. Mol. Ther. 33, 3360–3374 (2025).
Google Scholar
Ledergor, G. et al. CD4+ CAR T-cell exhaustion associated with early relapse of multiple myeloma after BCMA CAR T-cell therapy. Blood Adv. 8, 3562–3575 (2024).
Google Scholar
Wang, Y. et al. Characteristics of premanufacture CD8+ T cells determine CAR-T efficacy in patients with diffuse large B-cell lymphoma. Signal Transduct. Target Ther. 8, 409 (2023).
Google Scholar
Effros, R. B. Replicative senescence of CD8 T cells: effect on human ageing. Exp. Gerontol. 39, 517–524 (2004).
Google Scholar
Joseph, R. W. et al. Impact of clinical and pathologic features on tumor-infiltrating lymphocyte expansion from surgically excised melanoma metastases for adoptive T-cell therapy. Clin. Cancer Res. 17, 4882–4891 (2011).
Google Scholar
Kadyrzhanova, G. et al. Aging impairs CD8 T cell responses in adoptive T-cell therapy against solid tumors. Front. Immunol. 16, 1484303 (2025).
Google Scholar
Qi, S. et al. Impacts of ageing on the efficacy of CAR-T cell therapy. Ageing Res. Rev. 107, 102715 (2025).
Google Scholar
Cuffel, A. et al. Real-world characteristics of T-cell apheresis and clinical response to tisagenlecleucel in B-cell lymphoma. Blood Adv. 6, 4657–4660 (2022).
Google Scholar
Locke, F. L. et al. Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 4, 4898–4911 (2020).
Google Scholar
Junkuhn, C. et al. Prior chemotherapy deteriorates T-cell quality for CAR T-cell therapy in B-cell non-Hodgkin’s lymphoma. J. Immunother Cancer. 13, e010709 (2025).
Onyema, O. O. et al. Chemotherapy-induced changes and immunosenescence of CD8+ T-cells in patients with breast cancer. Anticancer Res. 35, 1481–1489 (2015).
Google Scholar
Chen, I. H. et al. Immune impairment in patients with terminal cancers: influence of cancer treatments and cytomegalovirus infection. Cancer Immunol. Immunother. 59, 323–334 (2010).
Google Scholar
Kientega, T. et al. Premature thymic functional senescence is a hallmark of childhood acute lymphoblastic leukemia survivorship. Blood Cancer J. 14, 96 (2024).
Google Scholar
Saavedra, D., Garcia, B. & Lage, A. T Cell Subpopulations in Healthy Elderly and Lung Cancer Patients: Insights from Cuban Studies. Front. Immunol. 8, 146 (2017).
Google Scholar
Coppola, G. et al. Ex vivo expansion of melanoma tumor infiltrating lymphocytes leads to a dominant exhausted T cell population with lack of memory markers. Cancer Immunol. Res. 14, 861–874 (2026).
Mescher, M. F. et al. Signals required for programming effector and memory development by CD8+ T cells. Immunol. Rev. 211, 81–92 (2006).
Google Scholar
Henson, S. M. et al. KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells. Blood 113, 6619–6628 (2009).
Google Scholar
Barrett, D. M. et al. Relation of clinical culture method to T-cell memory status and efficacy in xenograft models of adoptive immunotherapy. Cytotherapy 16, 619–630 (2014).
Google Scholar
Monteiro, J., Batliwalla, F., Ostrer, H. & Gregersen, P. K. Shortened telomeres in clonally expanded CD28-CD8+ T cells imply a replicative history that is distinct from their CD28+CD8+ counterparts. J. Immunol. 156, 3587–3590 (1996).
Google Scholar
Zhou, J. et al. Chimeric antigen receptor T (CAR-T) cells expanded with IL-7/IL-15 mediate superior antitumor effects. Protein Cell 10, 764–769 (2019).
Google Scholar
Salz, L. et al. Culture expansion of CAR T cells results in aberrant DNA methylation that is associated with adverse clinical outcome. Leukemia 37, 1868–1878 (2023).
Google Scholar
Vučinić, V. et al. Impact of cellular composition and T-cell senescence of mononuclear cell concentrates on the manufacturing process of chimeric antigen receptor (CAR) T-cells. Transfusion 65, 1650-1661 (2025).
Mo, F. et al. Human platelet lysate enhances in vivo activity of CAR-Vδ2 T cells by reducing cellular senescence and apoptosis. Cytotherapy 26, 858–868 (2024).
Google Scholar
Garcia, J. et al. Naturally occurring T cell mutations enhance engineered T cell therapies. Nature 626, 626–634 (2024).
Google Scholar
Obenaus, M. et al. Identification of human T-cell receptors with optimal affinity to cancer antigens using antigen-negative humanized mice. Nat. Biotechnol. 33, 402–407 (2015).
Google Scholar
Zhong, S. et al. T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy. Proc. Natl. Acad. Sci. USA 110, 6973–6978 (2013).
Google Scholar
Eggebø, M. S. et al. TCR-engineered T cells targeting a shared β-catenin mutation eradicate solid tumors. Nat. Immunol. 26, 1726–1736 (2025).
Google Scholar
Woolaver, R. A. et al. Differences in TCR repertoire and T cell activation underlie the divergent outcomes of antitumor immune responses in tumor-eradicating versus tumor-progressing hosts. J Immunother Cancer. 9, e001615 (2021).
Attuil, V. et al. Comparative T cell receptor repertoire selection by antigen after adoptive transfer: a glimpse at an antigen-specific preimmune repertoire. Proc. Natl. Acad. Sci. USA 97, 8473–8478 (2000).
Google Scholar
Sharma, P., Harris, D. T., Stone, J. D. & Kranz, D. M. T-cell Receptors Engineered de novo for peptide specificity can mediate optimal T-cell activity without self cross-reactivity. Cancer Immunol. Res. 7, 2025–2035 (2019).
Google Scholar
Morton, L. T. et al. Simultaneous Deletion of Endogenous TCRαβ for TCR Gene Therapy Creates an Improved and Safe Cellular Therapeutic. Mol. Ther. 28, 64–74 (2020).
Google Scholar
Kawalekar, O. U. et al. Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. Immunity 44, 712 (2016).
Google Scholar
Long, A. H. et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat. Med. 21, 581–590 (2015).
Google Scholar
Cappell, K. M. & Kochenderfer, J. N. A comparison of chimeric antigen receptors containing CD28 versus 4-1BB costimulatory domains. Nat. Rev. Clin. Oncol. 18, 715–727 (2021).
Google Scholar
Can, I. et al. Differential susceptibility and role for senescence in CART cells based on costimulatory domains. Mol. Cancer 24, 172 (2025).
Google Scholar
Xiao, Q. et al. Size-dependent activation of CAR-T cells. Sci. Immunol. 7, eabl3995 (2022).
Google Scholar
Watanabe, N. et al. Fine-tuning the CAR spacer improves T-cell potency. Oncoimmunology 5, e1253656 (2016).
Google Scholar
Yang, Y. et al. TCR engagement negatively affects CD8 but not CD4 CAR T cell expansion and leukemic clearance. Sci. Transl. Med. 9, eaag1209 (2017).
Salter, A. I. et al. Comparative analysis of TCR and CAR signaling informs CAR designs with superior antigen sensitivity and in vivo function. Sci. Signal. 14, eabe2606 (2021).
Wu, L., Wei, Q., Brzostek, J. & Gascoigne, N. R. J. Signaling from T cell receptors (TCRs) and chimeric antigen receptors (CARs) on T cells. Cell Mol. Immunol. 17, 600–612 (2020).
Google Scholar
Liseth, O. & Vile, R. The TCR in CAR T cell therapy: use it or lose it? Cancer Gene Ther. https://doi.org/10.1038/s41417-026-01018-7 (2026).
Zhu, X. & Niedermann, G. Rapid and efficient transfer of the T cell aging marker CD57 from glioblastoma stem cells to CAR T cells. Oncoscience 2, 476–482 (2015).
Google Scholar
Giraldo, N. A. et al. The clinical role of the TME in solid cancer. Br. J. Cancer 120, 45–53 (2019).
Google Scholar
Zhu, Y., Xu, K. & Wang, Y. Tumor microenvironment in CAR-T cell therapy for lymphoma. Best. Pr. Res Clin. Haematol. 38, 101635 (2025).
Google Scholar
García-Ortiz, A. et al. The Role of Tumor Microenvironment in Multiple Myeloma Development and Progression. Cancers 13, 217 (2021).
Ye, J. et al. Human regulatory T cells induce T-lymphocyte senescence. Blood 120, 2021–2031 (2012).
Google Scholar
Yang, Y. et al. Myeloid-Derived Suppressor Cells in Tumors: From Mechanisms to Antigen Specificity and Microenvironmental Regulation. Front Immunol. 11, 1371 (2020).
Google Scholar
Liu, J. et al. MDSCs-derived GPR84 induces CD8+ T cell senescence via p53 activation to suppress the antitumor response. J. Immunother Cancer. 11, e007802 (2023).
Towers, R. et al. Bone marrow-derived mesenchymal stromal cells obstruct AML-targeting CD8+ clonal effector and CAR T-cell function while promoting a senescence-associated phenotype. Cancer Immunol. Immunother. 73, 8 (2024).
Google Scholar
Yang, R. et al. Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with adenosine receptor A2A blockade. J. Immunother Cancer. 8, e000610 (2020).
Qu, Y. et al. Adenosine Deaminase 1 Overexpression Enhances the Antitumor Efficacy of Chimeric Antigen Receptor-Engineered T Cells. Hum. Gene Ther. 33, 223–236 (2022).
Google Scholar
Mandapathil, M. et al. Generation and accumulation of immunosuppressive adenosine by human CD4+CD25highFOXP3+ regulatory T cells. J. Biol. Chem. 285, 7176–7186 (2010).
Google Scholar
Parish, S. T. et al. Adenosine deaminase modulation of telomerase activity and replicative senescence in human CD8 T lymphocytes. J. Immunol. 184, 2847–2854 (2010).
Google Scholar
Alum, E. U. et al. Targeting Cellular Senescence for Healthy Aging: Advances in Senolytics and Senomorphics. Drug Des. Devel Ther. 19, 8489–8522 (2025).
Google Scholar
Zhang, L. et al. Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. FEBS J. 290, 1362–1383 (2023).
Google Scholar
Rufer, N. et al. Transfer of the human telomerase reverse transcriptase (TERT) gene into T lymphocytes results in extension of replicative potential. Blood 98, 597–603 (2001).
Google Scholar
Bai, Y. et al. Enhancement of the in vivo persistence and antitumor efficacy of CD19 chimeric antigen receptor T cells through the delivery of modified TERT mRNA. Cell Discov. 1, 15040 (2015).
Google Scholar
Huang, S., Lau, C. H., Tin, C. & Lam, R. H. W. Extended replicative lifespan of primary resting T cells by CRISPR/dCas9-based epigenetic modifiers and transcriptional activators. Cell Mol. Life Sci. 81, 407 (2024).
Google Scholar
Sugiyama, Y. et al. A senolytic immunotoxin eliminates p16(INK4a)-positive T cells and ameliorates age-associated phenotype of CD4+ T cells in a surface marker knock-in mouse. Exp. Gerontol. 174, 112130 (2023).
Google Scholar
Legscha, K. J. et al. Δ133p53α enhances metabolic and cellular fitness of TCR-engineered T cells and promotes superior antitumor immunity. J. Immunother Cancer. 9, e001846 (2021).
Fujita, K. et al. p53 isoforms Delta133p53 and p53beta are endogenous regulators of replicative cellular senescence. Nat. Cell Biol. 11, 1135–1142 (2009).
Google Scholar
Roselle, C. et al. Enhancing chimeric antigen receptor T cell therapy by modulating the p53 signaling network with Δ133p53α. Proc. Natl. Acad. Sci. USA 121, e2317735121 (2024).
Google Scholar
Jiang, J. et al. CD4+CD57+ senescent T cells as promoters of systemic lupus erhthematosus pathogenesis and the therapeutic potential of senolytic BCL-2 inhibitor. Eur. J. Immunol. 54, e2350603 (2024).
Google Scholar
Warrington, K. J., Vallejo, A. N., Weyand, C. M. & Goronzy, J. J. CD28 loss in senescent CD4+ T cells: reversal by interleukin-12 stimulation. Blood 101, 3543–3549 (2003).
Google Scholar
Parish, S. T., Wu, J. E. & Effros, R. B. Sustained CD28 expression delays multiple features of replicative senescence in human CD8 T lymphocytes. J. Clin. Immunol. 30, 798–805 (2010).
Google Scholar
Zhang, Y. et al. Interleukin-7 inhibits tumor-induced CD27-CD28- suppressor T cells: implications for cancer immunotherapy. Clin. Cancer Res 17, 4975–4986 (2011).
Google Scholar
Niu, C. et al. Foxp3 confers long-term efficacy of chimeric antigen receptor-T cells via metabolic reprogramming. Cell Metab. 37, 1426–1441.e1427 (2025).
Google Scholar
Zhang, C. et al. Autophagic flux restoration of senescent T cells improves antitumor activity of TCR-engineered T cells. Clin. Transl. Immunol. 11, e1419 (2022).
Google Scholar
Bai, X. F. et al. Click Chemistry-Assisted Rejuvenation of Aging T Cells Sensitizes Aged Mice to Tumor Immunotherapy. J. Am. Chem. Soc. 147, 16694–16704 (2025).
Google Scholar
Bulliard, Y. et al. Reprogramming T cell differentiation and exhaustion in CAR-T cell therapy. J. Hematol. Oncol. 16, 108 (2023).
Google Scholar
Van der Vreken, A. et al. Fueling CARs: metabolic strategies to enhance CAR T-cell therapy. Exp. Hematol. Oncol. 13, 66 (2024).
Google Scholar
Tedder, B. & Bhutani, M. Resistance Mechanisms to BCMA Targeting Bispecific Antibodies and CAR T-Cell Therapies in Multiple Myeloma. Cells. 14, 1077 (2025).
Poorebrahim, M. et al. Counteracting CAR T cell dysfunction. Oncogene 40, 421–435 (2021).
Google Scholar
Liu, X. et al. A novel dominant-negative PD-1 armored anti-CD19 CAR T cell is safe and effective against refractory/relapsed B cell lymphoma. Transl. Oncol. 14, 101085 (2021).
Google Scholar
Agarwal, S. et al. Deletion of the inhibitory co-receptor CTLA-4 enhances and invigorates chimeric antigen receptor T cells. Immunity 56, 2388–2407 e2389 (2023).
Google Scholar
Lynn, R. C. et al. c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature 576, 293–300 (2019).
Google Scholar
Zuo, S. et al. C-JUN overexpressing CAR-T cells in acute myeloid leukemia: preclinical characterization and phase I trial. Nat. Commun. 15, 6155 (2024).
Google Scholar
Chan, J. D. et al. FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy. Nature 629, 201–210 (2024).
Google Scholar
Doan, A. E. et al. FOXO1 is a master regulator of memory programming in CAR T cells. Nature 629, 211–218 (2024).
Google Scholar
Smole, A. et al. Expression of inducible factors reprograms CAR-T cells for enhanced function and safety. Cancer Cell 40, 1470–1487.e1477 (2022).
Google Scholar
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).
Google Scholar
Hu, G. & Chen, J. A genome-wide regulatory network identifies key transcription factors for memory CD8⁺ T-cell development. Nat. Commun. 4, 2830 (2013).
Google Scholar
Chang, T. C. et al. BACH2 regulates T cell lineage state to enhance CAR T cell function. Nat. Immunol. 27, 413–424 (2026).
Google Scholar
Hou, M. et al. Timosaponin AIII enhances CAR-T cell potency and prevents relapse through impairing CAR-Tregs. Nat. Commun. 17, 3045 (2026).
Tsai, C. T. et al. Enhancing CAR- and TCR-mediated targeting of cancer via an immune synapse-stabilizing receptor. Nat. Commun. 17, 1349 (2026).
Google Scholar
Itoh-Nakadai, A. et al. CXCR4 induces memory formation over exhaustion in CAR-T cells to achieve durable leukemia targeting. Nat. Commun. 17, 101 (2026).
Google Scholar
Fraietta, J. A. et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558, 307–312 (2018).
Google Scholar
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).
Google Scholar
Jain, N. et al. TET2 guards against unchecked BATF3-induced CAR T cell expansion. Nature 615, 315–322 (2023).
Google Scholar
Prinzing, B. et al. Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity. Sci. Transl. Med. 13, eabh0272 (2021).
Google Scholar
Jain, N. et al. Disruption of SUV39H1-Mediated H3K9 Methylation Sustains CAR T-cell Function. Cancer Discov. 14, 142–157 (2024).
Google Scholar
Zhu, M. et al. Class I HDAC inhibitors enhance antitumor efficacy and persistence of CAR-T cells by activation of the Wnt pathway. Cell Rep. 43, 114065 (2024).
Google Scholar
Lei, X. et al. A Pan-Histone Deacetylase Inhibitor Enhances the Antitumor Activity of B7-H3-Specific CAR T Cells in Solid Tumors. Clin. Cancer Res. 27, 3757–3771 (2021).
Google Scholar
Brudno, J. N. & Kochenderfer, J. N. Current understanding and management of CAR T cell-associated toxicities. Nat. Rev. Clin. Oncol. 21, 501–521 (2024).
Google Scholar
Wu, C. Y. et al. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science 350, aab4077 (2015).
Google Scholar
Jan, M. et al. Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide. Sci Transl Med. 13, eabb6295 (2021).
Weber, E. W. et al. Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling. Science. 372, eaba1786 (2021).
Weber, E. W. et al. Pharmacologic control of CAR-T cell function using dasatinib. Blood Adv. 3, 711–717 (2019).
Google Scholar
Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113–117 (2017).
Google Scholar
Webster, B. et al. Self-driving armored CAR-T cells overcome a suppressive milieu and eradicate CD19(+) Raji lymphoma in preclinical models. Mol. Ther. 29, 2691–2706 (2021).
Google Scholar
Choe, J. H. et al. SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma. Sci Transl Med. 13, eabe7378 (2021).
Roybal, K. T. et al. Engineering T Cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors. Cell 167, 419–432 e416 (2016).
Google Scholar
Adams, E. L. et al. Small-molecule control of CAR T cells. Nat. Rev. Chem. 9, 809–825 (2025).
Google Scholar
Ghassemi, S. et al. Rapid manufacturing of non-activated potent CAR T cells. Nat. Biomed. Eng. 6, 118–128 (2022).
Google Scholar
Yang, J. et al. Next-day manufacture of a novel anti-CD19 CAR-T therapy for B-cell acute lymphoblastic leukemia: first-in-human clinical study. Blood Cancer J. 12, 104 (2022).
Google Scholar
Harrington, P. et al. Differential inhibition of T-cell receptor and STAT5 signaling pathways determines the immunomodulatory effects of dasatinib in chronic phase chronic myeloid leukemia. Haematologica 108, 1555–1566 (2023).
Google Scholar
Saito, H. et al. Reprogramming of Melanoma Tumor-Infiltrating Lymphocytes to Induced Pluripotent Stem Cells. Stem Cells Int. 2016, 8394960 (2016).
Google Scholar
Nishimura, T. et al. Generation of rejuvenated antigen-specific T cells by reprogramming to pluripotency and redifferentiation. Cell Stem Cell 12, 114–126 (2013).
Google Scholar
Islam, S. M. R. et al. Reprogramming of Tumor-reactive Tumor-infiltrating Lymphocytes to Human-induced Pluripotent Stem Cells. Cancer Res. Commun. 3, 917–932 (2023).
Google Scholar
Itoh, M. et al. Generation of induced pluripotent stem cell (iPSC) from NY-ESO-I-specific cytotoxic T cells isolated from the melanoma patient with minor HLAs: The practical pilot study for the adoptive immunotherapy for melanoma using iPSC technology. Exp. Dermatol. 32, 126–134 (2023).
Google Scholar
Zahm, C. D. et al. TLR Stimulation during T-cell Activation Lowers PD-1 Expression on CD8+ T cells. Cancer Immunol. Res. 6, 1364–1374 (2018).
Google Scholar
Weng, J. et al. IL-15 enhances the antitumor effect of human antigen-specific CD8+ T cells by cellular senescence delay. Oncoimmunology 5, e1237327 (2016).
Google Scholar
Cieri, N. et al. IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood 121, 573–584 (2013).
Google Scholar
Nguyen, V., Mendelsohn, A. & Larrick, J. W. Interleukin-7 and Immunosenescence. J. Immunol. Res. 2017, 4807853 (2017).
Google Scholar
Yunger, S. et al. Modulating the proliferative and cytotoxic properties of patient-derived TIL by a synthetic immune niche of immobilized CCL21 and ICAM1. Front. Oncol. 13, 1116328 (2023).
Google Scholar
Klysz, D. D. et al. Inosine induces stemness features in CAR-T cells and enhances potency. Cancer Cell 42, 266–282.e268 (2024).
Google Scholar
Arcangeli, S. et al. CAR T cell manufacturing from naive/stem memory T lymphocytes enhances antitumor responses while curtailing cytokine release syndrome. J. Clin. Invest. 132, e150807 (2022).
Arcangeli, S. et al. Next-Generation Manufacturing Protocols Enriching T(SCM) CAR T cells can overcome disease-specific T cell defects in cancer patients. Front. Immunol. 11, 1217 (2020).
Google Scholar
Luo, Y. et al. Donor-derived Anti-CD19 CAR T cells GC007g for relapsed or refractory B-cell acute lymphoblastic leukemia after allogeneic HSCT: a phase 1 trial. EClinicalMedicine 67, 102377 (2024).
Google Scholar
Tseng, H. et al. T(SCM)-predominant allogeneic anti-BCMA CAR-T therapy for relapsed/refractory multiple myeloma: preclinical characterization and interim results from a phase 1 trial. Nat. Commun. 16, 10050 (2025).
Google Scholar
Jo, S. et al. Endowing universal CAR T-cell with immune-evasive properties using TALEN-gene editing. Nat. Commun. 13, 3453 (2022).
Google Scholar
Qasim, W. et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci. Transl. Med. 9, eaaj2013 (2017).
Liu, X. et al. CRISPR-Cas9-mediated multiplex gene editing in CAR-T cells. Cell Res. 27, 154–157 (2017).
Google Scholar
Wang, M. et al. Co-Delivery of Multiple RNAs via Lipid Nanoparticles Enables Precise Gene Editing of CAR-T Cells. Adv. Healthc. Mater. 15, e01475 (2025).
Tipanee, J. et al. Universal allogeneic CAR T cells engineered with Sleeping Beauty transposons and CRISPR-CAS9 for cancer immunotherapy. Mol. Ther. 30, 3155–3175 (2022).
Google Scholar
Kagoya, Y. et al. Genetic Ablation of HLA Class I, Class II, and the T-cell Receptor Enables Allogeneic T Cells to Be Used for Adoptive T-cell Therapy. Cancer Immunol. Res. 8, 926–936 (2020).
Google Scholar
Torikai, H. et al. Toward eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood 122, 1341–1349 (2013).
Google Scholar
Chen, X. et al. Allogeneic CAR-T cells with of HLA-A/B and TRAC disruption exhibit promising antitumor capacity against B cell malignancies. Cancer Immunol. Immunother. 73, 13 (2024).
Google Scholar
Benjamin, R. et al. UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM): a phase 1, dose-escalation trial. Lancet Haematol. 9, e833–e843 (2022).
Google Scholar
Ren, J. et al. Multiplex Genome Editing to Generate Universal CAR T Cells Resistant to PD1 Inhibition. Clin. Cancer Res. 23, 2255–2266 (2017).
Google Scholar
Choi, B. D. et al. CRISPR-Cas9 disruption of PD-1 enhances activity of universal EGFRvIII CAR T cells in a preclinical model of human glioblastoma. J. Immunother. Cancer 7, 304 (2019).
Google Scholar
Li, X. et al. Intrathecal CRISPR-edited allogeneic IL-13Rα2 CAR T Cells for recurrent high-grade Glioma: preclinical characterization and phase I trial. Nat. Commun. 17, 1362 (2026).
Google Scholar
Engel, N. W. et al. Quadruple adenine base-edited allogeneic CAR T cells outperform CRISPR/Cas9 nuclease-engineered T cells. Proc. Natl. Acad. Sci. USA 122, e2427216122 (2025).
Google Scholar
Chiesa, R. et al. Universal Base-Edited CAR7 T Cells for T-Cell Acute Lymphoblastic Leukemia. N. Engl. J. Med. 394, 152–165 (2026).
Google Scholar
Yu, T. et al. Cord blood-derived CD19-specific chimeric antigen receptor T cells: an off-the-shelf promising therapeutic option for treatment of diffuse large B-cell lymphoma. Front. Immunol. 14, 1139482 (2023).
Google Scholar
Georgiadis, C. et al. Umbilical cord blood T cells can be isolated and enriched by CD62L selection for use in ‘off the shelf’ chimeric antigen receptor T-cell therapies to widen transplant options. Haematologica 109, 3941–3951 (2024).
Google Scholar
Jing, R. et al. EZH1 repression generates mature iPSC-derived CAR T cells with enhanced antitumor activity. Cell Stem Cell 32, 670 (2025).
Google Scholar
Themeli, M. et al. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat. Biotechnol. 31, 928–933 (2013).
Google Scholar
Bae, J. et al. Differentiation of BCMA-specific induced pluripotent stem cells into rejuvenated CD8αβ+ T cells targeting multiple myeloma. Blood 143, 895–911 (2024).
Google Scholar
Xu, H. et al. Targeted Disruption of HLA Genes via CRISPR-Cas9 Generates iPSCs with Enhanced Immune Compatibility. Cell Stem Cell 24, 566–578.e567 (2019).
Google Scholar
Muroyama, Y. & Wherry, E. J. Memory T-Cell Heterogeneity and Terminology. Cold Spring Harb. Perspect. Biol. 13, a037929 (2021).
Aspinall, R. Does the immune system of a mouse age faster than the immune system of a human? Bioessays 21, 519–524 (1999).
Google Scholar
Akbar, A. N., Soares, M. V., Plunkett, F. J. & Salmon, M. Differential regulation of CD8+ T cell senescence in mice and men. Mech. Ageing Dev. 121, 69–76 (2000).
Google Scholar
Roth, A. et al. Telomerase levels control the lifespan of human T lymphocytes. Blood 102, 849–857 (2003).
Google Scholar
Huang, M. et al. T cell senescence: a new perspective on immunotherapy in lung cancer. Front. Immunol. 15, 1338680 (2024).
Google Scholar
Meng, X. et al. Immunological mechanisms of tolerance: Central, peripheral and the role of T and B cells. Asia Pac. Allergy 13, 175–186 (2023).
Google Scholar
Li, F. et al. Metabolic plasticity and regulation of T cell exhaustion. Immunology 167, 482–494 (2022).
Google Scholar
Escrig-Larena, J. I., Delgado-Pulido, S. & Mittelbrunn, M. Mitochondria during T cell aging. Semin. Immunol. 69, 101808 (2023).
Google Scholar
Ouyang, W. et al. PD-1 downregulation enhances CAR-T cell antitumor efficiency by preserving a cell memory phenotype and reducing exhaustion. J. Immunother Cancer. 12, e008429 (2024).
Al-Habsi, M. et al. Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice. Science 378, eabj3510 (2022).
Google Scholar
Yang, J. et al. The effect of metformin on senescence of T lymphocytes. Immun. Ageing 20, 73 (2023).
Google Scholar
Bharath, L. P. et al. Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation. Cell Metab. 32, 44–55.e46 (2020).
Google Scholar

