{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:48:53Z","timestamp":1791582533011,"version":"4.3.4"},"reference-count":123,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>\n                    T cell exhaustion is a central framework for explaining why antitumor T cell responses often fail despite persistent antigen exposure and immune infiltration. Rather than a single dysfunctional endpoint, exhaustion is increasingly understood as a structured and dynamic continuum of antigen-experienced CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell states that differ in proliferative capacity, effector potential, epigenetic constraint, metabolic fitness, and spatial distribution within tumors. This view has major therapeutic implications because clinically relevant interventions can remodel exhausted-state composition and function without fully restoring a non-exhausted identity. In this review, we examine the organization of exhausted T cell states from progenitor-like to terminal compartments and discuss how TOX-linked survival programs, epigenetic fixation, and tumor-imposed metabolic and spatial constraints stabilize exhausted fate under chronic stimulation. We highlight the role of progenitor exhausted T cells in sustaining therapeutic responsiveness, explain why reinvigoration after checkpoint blockade is often partial rather than transformative, and evaluate emerging strategies to modulate exhaustion dynamics, including combination immunotherapy and engineered control systems in CAR T cells. Together, these concepts support a shift from viewing exhaustion as a binary defect to understanding it as a constrained state system that can be measured, preserved, and selectively redirected. Defining which exhausted states remain productively controllable, and under what conditions, will be essential for developing more durable and mechanistically informed cancer immunotherapies.\n                  <\/jats:p>","DOI":"10.3389\/fcell.2026.1827716","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T05:34:39Z","timestamp":1778736879000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["T cell exhaustion landscapes and therapeutic modulation in cancer immunity"],"prefix":"10.3389","volume":"14","author":[{"given":"Jhommara","family":"Bautista","sequence":"first","affiliation":[{"name":"Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Am\u00e9ricas","place":["Quito, Ecuador"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9s","family":"L\u00f3pez-Cort\u00e9s","sequence":"additional","affiliation":[{"name":"Cancer Research Group (CRG), Faculty of Medicine, Universidad de Las Am\u00e9ricas","place":["Quito, Ecuador"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1038\/s41590-021-00975-5","article-title":"Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation","volume":"22","author":"Abdel-Hakeem","year":"2021","journal-title":"Nat. Immunol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"114650","DOI":"10.1016\/j.jconrel.2026.114650","article-title":"Next generation CAR-T cells to tackle solid tumors","volume":"391","author":"Abreu","year":"2026","journal-title":"J. Control. Release"},{"key":"B3","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/s41586-019-1326-9","article-title":"TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection","volume":"571","author":"Alfei","year":"2019","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2965","DOI":"10.1038\/s41467-021-23324-4","article-title":"Interpretation of T cell states from single-cell transcriptomics data using reference atlases","volume":"12","author":"Andreatta","year":"2021","journal-title":"Nat. Commun."},{"key":"B5","doi-asserted-by":"publisher","first-page":"3359","DOI":"10.4049\/jimmunol.1001836","article-title":"Evolution of ectopic lymphoid neogenesis and in situ autoantibody production in autoimmune nonobese diabetic mice: cellular and molecular characterization of tertiary lymphoid structures in pancreatic islets","volume":"185","author":"Astorri","year":"2010","journal-title":"J. Immunol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.jhep.2022.02.032","article-title":"T-cell exhaustion and residency dynamics inform clinical outcomes in hepatocellular carcinoma","volume":"77","author":"Barsch","year":"2022","journal-title":"J. Hepatol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1038\/s41586-025-09370-8","article-title":"Cancer-induced nerve injury promotes resistance to anti-PD-1 therapy","volume":"646","author":"Baruch","year":"2025","journal-title":"Nature"},{"key":"B8","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1038\/s41591-021-01323-8","article-title":"A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer","volume":"27","author":"Bassez","year":"2021","journal-title":"Nat. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1617198","DOI":"10.3389\/fcimb.2025.1617198","article-title":"Oncogenic viruses rewire the epigenome in human cancer","volume":"15","author":"Bautista","year":"2025","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1691172","DOI":"10.3389\/fendo.2025.1691172","article-title":"Chronobiome medicine: circadian regulation of host\u2013microbiota crosstalk in systemic physiology","volume":"16","author":"Bautista","year":"","journal-title":"Front. Endocrinol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1677481","DOI":"10.3389\/fcell.2025.1677481","article-title":"Deciphering organotropism reveals therapeutic targets in metastasis","volume":"13","author":"Bautista","year":"","journal-title":"Front. Cell Dev. Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"113550","DOI":"10.1016\/j.isci.2025.113550","article-title":"Neurodegeneration rewires the tumor microenvironment via the neuro-immune-cancer axis","volume":"28","author":"Bautista","year":"","journal-title":"iScience"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1606242","DOI":"10.3389\/fendo.2025.1606242","article-title":"Peripheral clocks and systemic zeitgeber interactions: from molecular mechanisms to circadian precision medicine","volume":"16","author":"Bautista","year":"","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e7864229","DOI":"10.1155\/jimr\/7864229","article-title":"Next\u2010generation immune checkpoints and tumor microenvironment modulation in cancer immunotherapy","volume":"2026","author":"Bautista","year":"2026","journal-title":"J. Immunol. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1016\/j.ccell.2022.06.001","article-title":"Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence","volume":"40","author":"Belk","year":"2022","journal-title":"Cancer Cell"},{"key":"B16","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1016\/j.immuni.2020.04.014","article-title":"Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms","volume":"52","author":"Beltra","year":"2020","journal-title":"Immunity"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2699","DOI":"10.1016\/j.immuni.2023.11.005","article-title":"Stat5 opposes the transcription factor Tox and rewires exhausted CD8+ T cells toward durable effector-like states during chronic antigen exposure","volume":"56","author":"Beltra","year":"2023","journal-title":"Immunity"},{"key":"B18","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/j.immuni.2016.07.008","article-title":"Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion","volume":"45","author":"Bengsch","year":"2016","journal-title":"Immunity"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1408","DOI":"10.1038\/s41587-020-0591-3","article-title":"Generalizing RNA velocity to transient cell states through dynamical modeling","volume":"38","author":"Bergen","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1038\/nature13323","article-title":"Aryl hydrocarbon receptor control of a disease tolerance defence pathway","volume":"511","author":"Bessede","year":"2014","journal-title":"Nature"},{"key":"B21","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1038\/s41591-018-0014-x","article-title":"Understanding the tumor immune microenvironment (TIME) for effective therapy","volume":"24","author":"Binnewies","year":"2018","journal-title":"Nat. Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1126\/science.aaf2834","article-title":"Cancer immunology. The \u201ccancer immunogram\u201d","volume":"352","author":"Blank","year":"2016","journal-title":"Science"},{"key":"B23","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1038\/s41577-019-0221-9","article-title":"Defining \u201cT cell exhaustion\u201d","volume":"19","author":"Blank","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1038\/s41586-021-03752-4","article-title":"Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers","volume":"596","author":"Caushi","year":"2021","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","first-page":"7217","DOI":"10.1038\/s41467-022-34897-z","article-title":"The circadian clock influences T cell responses to vaccination by regulating dendritic cell antigen processing","volume":"13","author":"Cervantes-Silva","year":"2022","journal-title":"Nat. Commun."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1016\/j.cell.2015.08.016","article-title":"Metabolic competition in the tumor microenvironment is a driver of cancer progression","volume":"162","author":"Chang","year":"2015","journal-title":"Cell"},{"key":"B27","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1038\/s41586-019-0985-x","article-title":"NR4A transcription factors limit CAR T cell function in solid tumours","volume":"567","author":"Chen","year":"2019","journal-title":"Nature"},{"key":"B28","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1038\/s41577-021-00541-y","article-title":"Metabolic barriers to cancer immunotherapy","volume":"21","author":"DePeaux","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1673","DOI":"10.1056\/NEJMoa1106152","article-title":"Inducible apoptosis as a safety switch for adoptive cell therapy","volume":"365","author":"Di Stasi","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1761","DOI":"10.1038\/s41423-020-0365-3","article-title":"Enforced PGC-1\u03b1 expression promotes CD8 T cell fitness, memory formation and antitumor immunity","volume":"18","author":"Dumauthioz","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2688","DOI":"10.1038\/s41467-019-10594-2","article-title":"Adenoviral vaccine targeting multiple neoantigens as strategy to eradicate large tumors combined with checkpoint blockade","volume":"10","author":"D\u2019Alise","year":"2019","journal-title":"Nat. Commun."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1158\/2159-8290.CD-23-1380","article-title":"Spatial architecture of myeloid and T cells orchestrates immune evasion and clinical outcome in lung cancer","volume":"14","author":"Enfield","year":"2024","journal-title":"Cancer Discov."},{"key":"B33","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1038\/nature21405","article-title":"Targeting a CAR to the TRAC locus with CRISPR\/Cas9 enhances tumour rejection","volume":"543","author":"Eyquem","year":"2017","journal-title":"Nature"},{"key":"B34","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/nm.4275","article-title":"Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B","volume":"23","author":"Fisicaro","year":"2017","journal-title":"Nat. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"6291","DOI":"10.4049\/jimmunol.1004030","article-title":"Circadian variation of the response of T cells to antigen","volume":"187","author":"Fortier","year":"2011","journal-title":"J. Immunol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1038\/s41591-018-0010-1","article-title":"Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia","volume":"24","author":"Fraietta","year":"2018","journal-title":"Nat. Med."},{"key":"B37","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1016\/j.ccell.2015.10.012","article-title":"Immunological effects of conventional chemotherapy and targeted anticancer agents","volume":"28","author":"Galluzzi","year":"2015","journal-title":"Cancer Cell"},{"key":"B38","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.cell.2017.06.007","article-title":"De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation","volume":"170","author":"Ghoneim","year":"2017","journal-title":"Cell"},{"key":"B39","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.celrep.2017.09.015","article-title":"Tonic 4-1BB costimulation in chimeric antigen receptors impedes T cell survival and is vector-dependent","volume":"21","author":"Gomes-Silva","year":"2017","journal-title":"Cell Rep."},{"key":"B40","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1038\/s41586-025-09655-y","article-title":"SARS-CoV-2 mRNA vaccines sensitize tumours to immune checkpoint blockade","volume":"647","author":"Grippin","year":"2025","journal-title":"Nature"},{"key":"B41","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/s41698-022-00279-3","article-title":"Durable complete response to neoantigen-loaded dendritic-cell vaccine following anti-PD-1 therapy in metastatic gastric cancer","volume":"6","author":"Guo","year":"2022","journal-title":"NPJ Precis. Oncol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1709852","DOI":"10.3389\/fimmu.2025.1709852","article-title":"Terminally exhausted CD8+ T cells in solid tumors: biology, biomarker potential and translational tools for precision oncology","volume":"16","author":"Guo","year":"2025","journal-title":"Front. Immunol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1038\/nm.3105","article-title":"Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion","volume":"19","author":"Hailemichael","year":"2013","journal-title":"Nat. Med."},{"key":"B44","doi-asserted-by":"publisher","first-page":"e52539","DOI":"10.7554\/eLife.52539","article-title":"SLAMF6\u200b deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel T cell checkpoint","volume":"9","author":"Hajaj","year":"2020","journal-title":"eLife"},{"key":"B45","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.canlet.2020.11.035","article-title":"TOX-expressing terminally exhausted tumor-infiltrating CD8+ T cells are reinvigorated by co-blockade of PD-1 and TIGIT in bladder cancer","volume":"499","author":"Han","year":"2021","journal-title":"Cancer Lett."},{"key":"B46","doi-asserted-by":"publisher","first-page":"277ra30","DOI":"10.1126\/scitranslmed.aaa1260","article-title":"Immunological mechanisms of the antitumor effects of supplemental oxygenation","volume":"7","author":"Hatfield","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1166","DOI":"10.1126\/science.abc1855","article-title":"T cell circuits that sense antigen density with an ultrasensitive threshold","volume":"371","author":"Hernandez-Lopez","year":"2021","journal-title":"Science"},{"key":"B48","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1038\/nature22079","article-title":"T-cell invigoration to tumour burden ratio associated with anti-PD-1 response","volume":"545","author":"Huang","year":"2017","journal-title":"Nature"},{"key":"B49","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nature19330","article-title":"Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy","volume":"537","author":"Im","year":"2016","journal-title":"Nature"},{"key":"B50","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1038\/s41586-019-1836-5","article-title":"An intra-tumoral niche maintains and differentiates stem-like CD8 T cells","volume":"576","author":"Jansen","year":"2019","journal-title":"Nature"},{"key":"B51","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1038\/s41586-019-1325-x","article-title":"TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion","volume":"571","author":"Khan","year":"2019","journal-title":"Nature"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1877","DOI":"10.1038\/s41590-025-02308-2","article-title":"Cancer vaccines as enablers of immunotherapy","volume":"26","author":"Khleif","year":"2025","journal-title":"Nat. Immunol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1016\/j.cmet.2019.08.013","article-title":"Mechanisms and implications of metabolic heterogeneity in cancer","volume":"30","author":"Kim","year":"2019","journal-title":"Cell Metab."},{"key":"B54","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1016\/j.immuni.2013.07.013","article-title":"The transcription factor Foxo1 controls central-memory CD8+ T cell responses to infection","volume":"39","author":"Kim","year":"2013","journal-title":"Immunity"},{"key":"B55","doi-asserted-by":"publisher","first-page":"1652047","DOI":"10.3389\/fcell.2025.1652047","article-title":"Reprogramming cancer immunity with next-generation combination therapies","volume":"13","author":"Kyriakidis","year":"2025","journal-title":"Front. Cell Dev. Biol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1038\/s41586-018-0414-6","article-title":"RNA velocity of single cells","volume":"560","author":"La Manno","year":"2018","journal-title":"Nature"},{"key":"B57","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1056\/NEJMoa1504030","article-title":"Combined nivolumab and ipilimumab or monotherapy in untreated melanoma","volume":"373","author":"Larkin","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"B58","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.1126\/science.271.5256.1734","article-title":"Enhancement of antitumor immunity by CTLA-4 blockade","volume":"271","author":"Leach","year":"1996","journal-title":"Science"},{"key":"B59","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1016\/j.cell.2018.11.043","article-title":"Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human Melanoma","volume":"176","author":"Li","year":"2019","journal-title":"Cell"},{"key":"B60","doi-asserted-by":"publisher","first-page":"4228","DOI":"10.1038\/s41467-025-59341-w","article-title":"Mature tertiary lymphoid structures evoke intra-tumoral T and B cell responses via progenitor exhausted CD4+ T cells in head and neck cancer","volume":"16","author":"Li","year":"2025","journal-title":"Nat. Commun."},{"key":"B61","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1038\/s41586-026-10106-5","article-title":"SLAMF6 as a drug-targetable suppressor of T cell immunity against cancer","volume":"652","author":"Li","year":"2026","journal-title":"Nature"},{"key":"B62","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/nm.3838","article-title":"4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors","volume":"21","author":"Long","year":"2015","journal-title":"Nat. Med."},{"key":"B63","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1038\/s41576-021-00370-8","article-title":"Integrating single-cell and spatial transcriptomics to elucidate intercellular tissue dynamics","volume":"22","author":"Longo","year":"2021","journal-title":"Nat. Rev. Genet."},{"key":"B64","doi-asserted-by":"publisher","first-page":"11100","DOI":"10.1038\/s41598-022-15246-y","article-title":"The close interaction between hypoxia-related proteins and metastasis in pancarcinomas","volume":"12","author":"L\u00f3pez-Cort\u00e9s","year":"2022","journal-title":"Sci. Rep."},{"key":"B65","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/s41586-019-1805-z","article-title":"c-Jun overexpression in CAR T cells induces exhaustion resistance","volume":"576","author":"Lynn","year":"2019","journal-title":"Nature"},{"key":"B66","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1016\/j.immuni.2017.11.021","article-title":"Transcription Factor IRF4 promotes CD8+ T cell exhaustion and limits the development of memory-like T cells during chronic infection","volume":"47","author":"Man","year":"2017","journal-title":"Immunity"},{"key":"B67","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.immuni.2015.01.006","article-title":"The transcription factor NFAT promotes exhaustion of activated CD8+ T cells","volume":"42","author":"Martinez","year":"2015","journal-title":"Immunity"},{"key":"B68","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1038\/s41571-019-0218-0","article-title":"Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance","volume":"16","author":"Martins","year":"2019","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"B69","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1038\/s41590-019-0312-6","article-title":"Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade","volume":"20","author":"Miller","year":"2019","journal-title":"Nat. Immunol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"E2776","DOI":"10.1073\/pnas.1620498114","article-title":"Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells","volume":"114","author":"Mognol","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B71","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.immuni.2005.03.013","article-title":"GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase","volume":"22","author":"Munn","year":"2005","journal-title":"Immunity"},{"key":"B72","doi-asserted-by":"publisher","first-page":"1381168","DOI":"10.3389\/fphar.2024.1381168","article-title":"The pharmacoepigenetic paradigm in cancer treatment","volume":"15","author":"Oca\u00f1a-Paredes","year":"2024","journal-title":"Front. Pharmacol."},{"key":"B73","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1038\/414916a","article-title":"Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage","volume":"414","author":"Ohta","year":"2001","journal-title":"Nature"},{"key":"B74","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1038\/s41586-021-03704-y","article-title":"Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma","volume":"596","author":"Oliveira","year":"2021","journal-title":"Nature"},{"key":"B75","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/nature10491","article-title":"An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor","volume":"478","author":"Opitz","year":"2011","journal-title":"Nature"},{"key":"B76","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1038\/nature22991","article-title":"An immunogenic personal neoantigen vaccine for patients with melanoma","volume":"547","author":"Ott","year":"2017","journal-title":"Nature"},{"key":"B77","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1126\/science.aaf2807","article-title":"Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade","volume":"354","author":"Pauken","year":"2016","journal-title":"Science"},{"key":"B78","doi-asserted-by":"publisher","first-page":"4734","DOI":"10.1016\/j.cell.2021.08.003","article-title":"Spatially organized multicellular immune hubs in human colorectal cancer","volume":"184","author":"Pelka","year":"2021","journal-title":"Cell"},{"key":"B79","doi-asserted-by":"publisher","first-page":"14198","DOI":"10.1038\/s41598-023-39401-1","article-title":"Integrated multi-omics analysis reveals the molecular interplay between circadian clocks and cancer pathogenesis","volume":"13","author":"P\u00e9rez-Villa","year":"2023","journal-title":"Sci. Rep."},{"key":"B80","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1038\/nature22367","article-title":"Chromatin states define tumour-specific T cell dysfunction and reprogramming","volume":"545","author":"Philip","year":"2017","journal-title":"Nature"},{"key":"B81","doi-asserted-by":"publisher","first-page":"2477","DOI":"10.1016\/j.molcel.2021.03.045","article-title":"A unified atlas of CD8 T cell dysfunctional states in cancer and infection","volume":"81","author":"Pritykin","year":"2021","journal-title":"Mol. Cell"},{"key":"B82","doi-asserted-by":"publisher","first-page":"1053120","DOI":"10.3389\/fimmu.2022.1053120","article-title":"Enhancing CAR T-cell therapies against solid tumors: mechanisms and reversion of resistance","volume":"13","author":"Qin","year":"2022","journal-title":"Front. Immunol."},{"key":"B83","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1016\/j.cell.2023.02.021","article-title":"Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes","volume":"186","author":"Rahim","year":"2023","journal-title":"Cell"},{"key":"B84","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1038\/s41586-023-06063-y","article-title":"Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer","volume":"618","author":"Rojas","year":"2023","journal-title":"Nature"},{"key":"B85","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1016\/j.cell.2018.10.038","article-title":"Defining T cell States associated with response to checkpoint immunotherapy in Melanoma","volume":"175","author":"Sade-Feldman","year":"2018","journal-title":"Cell"},{"key":"B86","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1038\/s41587-019-0071-9","article-title":"A comparison of single-cell trajectory inference methods","volume":"37","author":"Saelens","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"B87","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1038\/s41587-019-0206-z","article-title":"Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion","volume":"37","author":"Satpathy","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"B88","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1038\/s41568-019-0144-6","article-title":"Tertiary lymphoid structures in the era of cancer immunotherapy","volume":"19","author":"Saut\u00e8s-Fridman","year":"2019","journal-title":"Nat. Rev. Cancer"},{"key":"B89","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1016\/j.immuni.2016.07.009","article-title":"The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction","volume":"45","author":"Scharping","year":"2016","journal-title":"Immunity"},{"key":"B90","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/j.immuni.2016.07.011","article-title":"Tumor-Specific T cell dysfunction is a Dynamic Antigen-driven differentiation Program initiated early during tumorigenesis","volume":"45","author":"Schietinger","year":"2016","journal-title":"Immunity"},{"key":"B91","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1016\/j.cell.2020.10.021","article-title":"Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front","volume":"183","author":"Sch\u00fcrch","year":"2020","journal-title":"Cell"},{"key":"B92","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/s41586-019-1324-y","article-title":"TOX is a critical regulator of tumour-specific T cell differentiation","volume":"571","author":"Scott","year":"2019","journal-title":"Nature"},{"key":"B93","doi-asserted-by":"publisher","first-page":"101954","DOI":"10.1016\/j.xpro.2022.101954","article-title":"Inducing T cell dysfunction by chronic stimulation of CAR-engineered T cells targeting cancer cells in suspension cultures","volume":"4","author":"Selli","year":"2023","journal-title":"Star. Protoc."},{"key":"B94","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1126\/science.aae0491","article-title":"The epigenetic landscape of T cell exhaustion","volume":"354","author":"Sen","year":"2016","journal-title":"Science"},{"key":"B95","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.immuni.2018.12.021","article-title":"Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy","volume":"50","author":"Siddiqui","year":"2019","journal-title":"Immunity"},{"key":"B96","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1158\/0008-5472.CAN-17-1987","article-title":"Germinal centers determine the prognostic relevance of tertiary lymphoid structures and are impaired by corticosteroids in lung squamous cell carcinoma","volume":"78","author":"Sili\u0146a","year":"2018","journal-title":"Cancer Res."},{"key":"B97","doi-asserted-by":"publisher","first-page":"100620","DOI":"10.1016\/j.xcrm.2022.100620","article-title":"Distinct phenotypic states and spatial distribution of CD8+ T cell clonotypes in human brain metastases","volume":"3","author":"Sudmeier","year":"2022","journal-title":"Cell Rep. Med."},{"key":"B98","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1056\/NEJMoa2109970","article-title":"Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma","volume":"386","author":"Tawbi","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"B99","doi-asserted-by":"publisher","first-page":"e2309088","DOI":"10.1002\/advs.202309088","article-title":"Synthetic gene circuits for regulation of next-generation cell-based therapeutics","volume":"11","author":"Teixeira","year":"2024","journal-title":"Adv. Sci. (Weinh)"},{"key":"B100","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1038\/s41591-018-0057-z","article-title":"A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade","volume":"24","author":"Thommen","year":"2018","journal-title":"Nat. Med."},{"key":"B101","doi-asserted-by":"publisher","first-page":"101640","DOI":"10.1016\/j.xcrm.2024.101640","article-title":"Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity","volume":"5","author":"Tooley","year":"2024","journal-title":"Cell Rep. Med."},{"key":"B102","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1038\/nature14292","article-title":"Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer","volume":"520","author":"Twyman-Saint Victor","year":"2015","journal-title":"Nature"},{"key":"B103","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.immuni.2016.07.021","article-title":"T cell factor 1-expressing memory-like CD8(+) T cells sustain the immune response to chronic viral infections","volume":"45","author":"Utzschneider","year":"2016","journal-title":"Immunity"},{"key":"B104","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1038\/nm934","article-title":"Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase","volume":"9","author":"Uyttenhove","year":"2003","journal-title":"Nat. Med."},{"key":"B105","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1038\/s41590-020-0725-2","article-title":"Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen","volume":"21","author":"Vardhana","year":"2020","journal-title":"Nat. Immunol."},{"key":"B106","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/j.ccell.2023.01.004","article-title":"Intratumoral CD8+ T cells with a tissue-resident memory phenotype mediate local immunity and immune checkpoint responses in breast cancer","volume":"41","author":"Virassamy","year":"2023","journal-title":"Cancer Cell"},{"key":"B107","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/j.jhep.2019.05.015","article-title":"TOX promotes the exhaustion of antitumor CD8+ T cells by preventing PD1 degradation in hepatocellular carcinoma","volume":"71","author":"Wang","year":"2019","journal-title":"J. Hepatol."},{"key":"B108","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1038\/s41586-022-05605-0","article-title":"Dendritic cells direct circadian anti-tumour immune responses","volume":"614","author":"Wang","year":"2023","journal-title":"Nature"},{"key":"B109","doi-asserted-by":"publisher","first-page":"2690","DOI":"10.1016\/j.cell.2024.04.015","article-title":"Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy","volume":"187","author":"Wang","year":"2024","journal-title":"Cell"},{"key":"B110","doi-asserted-by":"publisher","first-page":"eaba1786","DOI":"10.1126\/science.aba1786","article-title":"Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling","volume":"372","author":"Weber","year":"2021","journal-title":"Science"},{"key":"B111","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1038\/ni.2035","article-title":"T cell exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat. Immunol."},{"key":"B112","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/nri3862","article-title":"Molecular and cellular insights into T cell exhaustion","volume":"15","author":"Wherry","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"B113","doi-asserted-by":"publisher","first-page":"aab4077","DOI":"10.1126\/science.aab4077","article-title":"Remote control of therapeutic T cells through a small molecule-gated chimeric receptor","volume":"350","author":"Wu","year":"2015","journal-title":"Science"},{"key":"B114","doi-asserted-by":"publisher","first-page":"eaai8593","DOI":"10.1126\/sciimmunol.aai8593","article-title":"The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness","volume":"1","author":"Wu","year":"2016","journal-title":"Sci. Immunol."},{"key":"B115","doi-asserted-by":"publisher","first-page":"2451","DOI":"10.3389\/fimmu.2019.02451","article-title":"Pan-cancer analysis reveals disrupted circadian clock associates with T cell exhaustion","volume":"10","author":"Wu","year":"2019","journal-title":"Front. Immunol."},{"key":"B116","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1038\/s41392-025-02327-3","article-title":"Revitalizing T cells: breakthroughs and challenges in overcoming T cell exhaustion","volume":"11","author":"Wu","year":"2026","journal-title":"Signal Transduct. Target. Ther."},{"key":"B117","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1038\/s41590-019-0403-4","article-title":"Single-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection","volume":"20","author":"Yao","year":"2019","journal-title":"Nat. Immunol."},{"key":"B118","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1038\/s41591-019-0522-3","article-title":"Clonal replacement of tumor-specific T cells following PD-1 blockade","volume":"25","author":"Yost","year":"2019","journal-title":"Nat. Med."},{"key":"B119","doi-asserted-by":"publisher","first-page":"134.14","DOI":"10.4049\/jimmunol.202.Supp.134.14","article-title":"De novo DNA methylation programs regulate T cell exhaustion and limit T cell-based immunotherapies","volume":"202","author":"Youngblood","year":"2019","journal-title":"J. Immunol."},{"key":"B120","doi-asserted-by":"publisher","first-page":"2205","DOI":"10.1084\/jem.188.12.2205","article-title":"Viral immune evasion due to persistence of activated T cells without effector function","volume":"188","author":"Zajac","year":"1998","journal-title":"J. Exp. Med."},{"key":"B121","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/s41420-024-01960-1","article-title":"Circadian rhythm regulates the function of immune cells and participates in the development of tumors","volume":"10","author":"Zeng","year":"2024","journal-title":"Cell Death Discov."},{"key":"B122","doi-asserted-by":"publisher","first-page":"104207","DOI":"10.1016\/j.ebiom.2022.104207","article-title":"Pan-cancer landscape of T-cell exhaustion heterogeneity within the tumor microenvironment revealed a progressive roadmap of hierarchical dysfunction associated with prognosis and therapeutic efficacy","volume":"83","author":"Zhang","year":"2022","journal-title":"EBioMedicine"},{"key":"B123","doi-asserted-by":"publisher","first-page":"abe6474","DOI":"10.1126\/science.abe6474","article-title":"Pan-cancer single-cell landscape of tumor-infiltrating T cells","volume":"374","author":"Zheng","year":"2021","journal-title":"Science"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1827716\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T05:34:41Z","timestamp":1778736881000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1827716\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,14]]},"references-count":123,"alternative-id":["10.3389\/fcell.2026.1827716"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1827716","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,14]]},"article-number":"1827716"}}