{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T18:51:06Z","timestamp":1793645466877,"version":"4.5.1"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Universitat de Barcelona","id":[{"id":"https:\/\/ror.org\/021018s57","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Transl Oncol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Chimeric antigen receptor (CAR) T cell therapies have demonstrated remarkable efficacy in hematologic malignancies; however, their clinical benefit in solid tumors remains limited. A major barrier is T cell dysfunction, particularly exhaustion and senescence, which impair persistence, effector function, and durable tumor control. Targeting these dysfunctional states is therefore essential in order to improve CAR T cell efficacy in solid tumors.<\/jats:p>\n                  <jats:p>This review summarizes recent preclinical strategies aimed at preventing or reversing CAR T cell exhaustion and senescence in solid malignancies. While both exhaustion and senescence are relevant dysfunctional states, the preclinical evidence summarized in this review is currently more extensive for modulation of exhaustion-associated programs than for direct reversal of canonical T cell senescence. Approaches are organized according to their primary mechanistic focus, including gene editing, metabolic modulation, receptor redesign, and remodeling of the tumor microenvironment.<\/jats:p>\n                  <jats:p>Across these mechanistic categories, reported benefits include enhanced CAR T cell persistence, reduced expression of inhibitory receptors, such as PD-1, LAG-3, and TIM-3, preservation or restoration of memory-like phenotypes, and improved antitumor cytotoxicity. Notably, combinatorial strategies targeting multiple dysfunction pathways consistently demonstrate superior efficacy in preclinical models. Despite these advances, important translational challenges remain, including the limited predictive value of current preclinical systems, potential safety concerns, and the manufacturing complexity associated with increasingly engineered cell products.<\/jats:p>\n                  <jats:p>Collectively, preclinical evidence supports the rational integration of complementary approaches to generate next-generation CAR T cells capable of resisting dysfunction and maintaining activity within immunosuppressive solid tumor microenvironments. Further validation in clinically relevant models will be critical to facilitate translation into safe and durable cancer immunotherapies.<\/jats:p>","DOI":"10.1007\/s12094-026-04383-9","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T14:15:27Z","timestamp":1778163327000},"page":"4533-4545","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Overcoming T cell exhaustion and senescence in CAR T cell therapy for solid tumors"],"prefix":"10.1007","volume":"28","author":[{"given":"Ignacio","family":"P\u00e9rez-Criado","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7563-3812","authenticated-orcid":false,"given":"Mariona","family":"Figols","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainhoa","family":"Moya-Sevilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Bautista","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"G\u00f3mez-D\u00edaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Font","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Martin-Liberal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4352-1784","authenticated-orcid":false,"given":"Vicen\u00e7","family":"Ruiz de Porras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"4383_CR1","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/j.cell.2015.03.030","volume":"161","author":"P Sharma","year":"2015","unstructured":"Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161:205\u201314. https:\/\/doi.org\/10.1016\/j.cell.2015.03.030.","journal-title":"Cell"},{"key":"4383_CR2","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1158\/2159-8290.CD-18-0367","volume":"8","author":"SC Wei","year":"2018","unstructured":"Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 2018;8:1069\u201386. https:\/\/doi.org\/10.1158\/2159-8290.CD-18-0367.","journal-title":"Cancer Discov"},{"key":"4383_CR3","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-025-02269-w","volume":"10","author":"I Zugasti","year":"2025","unstructured":"Zugasti I, Espinosa-Aroca L, Fidyt K, Mulens-Arias V, Diaz-Beya M, Juan M, et al. CAR-T cell therapy for cancer: current challenges and future directions. Signal Transduct Target Ther. 2025;10:210. https:\/\/doi.org\/10.1038\/s41392-025-02269-w.","journal-title":"Signal Transduct Target Ther"},{"key":"4383_CR4","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1126\/science.aar6711","volume":"359","author":"CH June","year":"2018","unstructured":"June CH, O\u2019Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Sci. 2018;359:1361\u20135. https:\/\/doi.org\/10.1126\/science.aar6711.","journal-title":"Sci"},{"key":"4383_CR5","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1146\/annurev-med-062315-120245","volume":"68","author":"K Newick","year":"2017","unstructured":"Newick K, O\u2019Brien S, Moon E, Albelda SM. CAR T Cell therapy for solid tumors. Annu Rev Med. 2017;68:139\u201352. https:\/\/doi.org\/10.1146\/annurev-med-062315-120245.","journal-title":"Annu Rev Med"},{"key":"4383_CR6","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1038\/s41571-019-0297-y","volume":"17","author":"S Rafiq","year":"2020","unstructured":"Rafiq S, Hackett CS, Brentjens RJ. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat Rev Clin Oncol. 2020;17:147\u201367. https:\/\/doi.org\/10.1038\/s41571-019-0297-y.","journal-title":"Nat Rev Clin Oncol"},{"key":"4383_CR7","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.1038\/s41591-018-0212-6","volume":"24","author":"S Rafiq","year":"2018","unstructured":"Rafiq S, Brentjens RJ. Tumors evading CARs-the chase is on. Nat Med. 2018;24:1492\u20133. https:\/\/doi.org\/10.1038\/s41591-018-0212-6.","journal-title":"Nat Med"},{"issue":"1","key":"4383_CR8","doi-asserted-by":"publisher","first-page":"1899469","DOI":"10.1080\/2162402X.2021.1899469","volume":"10","author":"SE Cha","year":"2021","unstructured":"Cha SE, Kujawski M, P JY, Brown C, Shively JE. Tumor regression and immunity in combination therapy with anti-CEA chimeric antigen receptor T cells and anti-CEA-IL2 immunocytokine. Oncoimmunology. 2021;10(1):1899469. https:\/\/doi.org\/10.1080\/2162402X.2021.1899469.","journal-title":"Oncoimmunology"},{"key":"4383_CR9","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1038\/s41586-022-04585-5","volume":"604","author":"RC Larson","year":"2022","unstructured":"Larson RC, Kann MC, Bailey SR, Haradhvala NJ, Llopis PM, Bouffard AA, et al. CAR T cell killing requires the IFNgammaR pathway in solid but not liquid tumours. Nat. 2022;604:563\u201370. https:\/\/doi.org\/10.1038\/s41586-022-04585-5.","journal-title":"Nat"},{"key":"4383_CR10","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/nm.3838","volume":"21","author":"AH Long","year":"2015","unstructured":"Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015;21:581\u201390. https:\/\/doi.org\/10.1038\/nm.3838.","journal-title":"Nat Med"},{"key":"4383_CR11","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.it.2015.02.008","volume":"36","author":"KE Pauken","year":"2015","unstructured":"Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 2015;36:265\u201376. https:\/\/doi.org\/10.1016\/j.it.2015.02.008.","journal-title":"Trends Immunol"},{"key":"4383_CR12","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1038\/s41571-019-0184-6","volume":"16","author":"NN Shah","year":"2019","unstructured":"Shah NN, Fry TJ. Mechanisms of resistance to CAR T cell therapy. Nat Rev Clin Oncol. 2019;16:372\u201385. https:\/\/doi.org\/10.1038\/s41571-019-0184-6.","journal-title":"Nat Rev Clin Oncol"},{"key":"4383_CR13","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-021-02221-0","volume":"41","author":"S Mishra","year":"2022","unstructured":"Mishra S, Charan M, Shukla RK, Agarwal P, Misri S, Verma AK, et al. cPLA2 blockade attenuates S100A7-mediated breast tumorigenicity by inhibiting the immunosuppressive tumor microenvironment. J Exp Clin Cancer Res. 2022;41:54. https:\/\/doi.org\/10.1186\/s13046-021-02221-0.","journal-title":"J Exp Clin Cancer Res"},{"issue":"3","key":"4383_CR14","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1038\/s41590-020-00850-9","volume":"22","author":"Y Liu","year":"2021","unstructured":"Liu Y, Zhou N, Zhou L, Wang J, Zhou Y, Zhang T, et al. IL-2 regulates tumor-reactive CD8(+) T cell exhaustion by activating the aryl hydrocarbon receptor. Nat Immunol. 2021;22(3):358\u201369. https:\/\/doi.org\/10.1038\/s41590-020-00850-9.","journal-title":"Nat Immunol"},{"key":"4383_CR15","first-page":"1535","volume":"13","author":"D Wu","year":"2021","unstructured":"Wu D, Zhu Y. Role of kynurenine in promoting the generation of exhausted CD8(+) T cells in colorectal cancer. Am J Transl Res. 2021;13:1535\u201347.","journal-title":"Am J Transl Res"},{"key":"4383_CR16","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1111\/imm.13642","volume":"169","author":"X Yin","year":"2023","unstructured":"Yin X, He L, Guo Z. T-cell exhaustion in CAR-T-cell therapy and strategies to overcome it. Immunol. 2023;169:400\u201311. https:\/\/doi.org\/10.1111\/imm.13642.","journal-title":"Immunol"},{"key":"4383_CR17","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1016\/j.ccell.2021.06.012","volume":"39","author":"GM Delgoffe","year":"2021","unstructured":"Delgoffe GM, Xu C, Mackall CL, Green MR, Gottschalk S, Speiser DE, et al. The role of exhaustion in CAR T cell therapy. Cancer Cell. 2021;39:885\u20138. https:\/\/doi.org\/10.1016\/j.ccell.2021.06.012.","journal-title":"Cancer Cell"},{"key":"4383_CR18","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202451093","volume":"54","author":"H Wu","year":"2024","unstructured":"Wu H, Li J, Zhang Z, Zhang Y. Characteristics and mechanisms of T-cell senescence: a potential target for cancer immunotherapy. Eur J Immunol. 2024;54:e2451093. https:\/\/doi.org\/10.1002\/eji.202451093.","journal-title":"Eur J Immunol"},{"key":"4383_CR19","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/s41423-019-0344-8","volume":"17","author":"Y Zhao","year":"2020","unstructured":"Zhao Y, Shao Q, Peng G. Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment. Cell Mol Immunol. 2020;17:27\u201335. https:\/\/doi.org\/10.1038\/s41423-019-0344-8.","journal-title":"Cell Mol Immunol"},{"key":"4383_CR20","doi-asserted-by":"publisher","DOI":"10.1111\/acel.70055","volume":"24","author":"TD Admasu","year":"2025","unstructured":"Admasu TD, Yu JS. Harnessing immune rejuvenation: advances in overcoming T cell senescence and exhaustion in cancer immunotherapy. Aging Cell. 2025;24:e70055. https:\/\/doi.org\/10.1111\/acel.70055.","journal-title":"Aging Cell"},{"key":"4383_CR21","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1038\/s42255-021-00483-8","volume":"3","author":"CD Wiley","year":"2021","unstructured":"Wiley CD, Campisi J. The metabolic roots of senescence: mechanisms and opportunities for intervention. Nat Metab. 2021;3:1290\u2013301. https:\/\/doi.org\/10.1038\/s42255-021-00483-8.","journal-title":"Nat Metab"},{"key":"4383_CR22","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1038\/s41589-022-01017-3","volume":"18","author":"SA Lim","year":"2022","unstructured":"Lim SA, Su W, Chapman NM, Chi H. Lipid metabolism in T cell signaling and function. Nat Chem Biol. 2022;18:470\u201381. https:\/\/doi.org\/10.1038\/s41589-022-01017-3.","journal-title":"Nat Chem Biol"},{"issue":"587","key":"4383_CR23","doi-asserted-by":"publisher","first-page":"eaaz6314","DOI":"10.1126\/scitranslmed.aaz6314","volume":"13","author":"X Liu","year":"2021","unstructured":"Liu X, Hartman CL, Li L, Albert CJ, Si F, Gao A, et al. Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy. Sci Transl Med. 2021;13(587):eaaz6314. https:\/\/doi.org\/10.1126\/scitranslmed.aaz6314.","journal-title":"Sci Transl Med"},{"key":"4383_CR24","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1038\/nature17412","volume":"531","author":"W Yang","year":"2016","unstructured":"Yang W, Bai Y, Xiong Y, Zhang J, Chen S, Zheng X, et al. Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism. Nat. 2016;531:651\u20135. https:\/\/doi.org\/10.1038\/nature17412.","journal-title":"Nat"},{"key":"4383_CR25","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1038\/ni.2570","volume":"14","author":"Y Kidani","year":"2013","unstructured":"Kidani Y, Elsaesser H, Hock MB, Vergnes L, Williams KJ, Argus JP, et al. Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat Immunol. 2013;14:489\u201399. https:\/\/doi.org\/10.1038\/ni.2570.","journal-title":"Nat Immunol"},{"issue":"6","key":"4383_CR26","doi-asserted-by":"publisher","first-page":"1376","DOI":"10.1016\/j.cmet.2019.02.016","volume":"29","author":"P Goossens","year":"2019","unstructured":"Goossens P, Rodriguez-Vita J, Etzerodt A, Masse M, Rastoin O, Gouirand V, et al. Membrane cholesterol efflux drives tumor-associated macrophage reprogramming and tumor progression. Cell Metab. 2019;29(6):1376\u201389. https:\/\/doi.org\/10.1016\/j.cmet.2019.02.016.","journal-title":"Cell Metab"},{"key":"4383_CR27","doi-asserted-by":"publisher","first-page":"1438","DOI":"10.1158\/0008-5472.CAN-19-2994","volume":"80","author":"P Su","year":"2020","unstructured":"Su P, Wang Q, Bi E, Ma X, Liu L, Yang M, et al. Enhanced lipid accumulation and metabolism are required for the differentiation and activation of tumor-associated macrophages. Cancer Res. 2020;80:1438\u201350. https:\/\/doi.org\/10.1158\/0008-5472.CAN-19-2994.","journal-title":"Cancer Res"},{"issue":"1","key":"4383_CR28","doi-asserted-by":"publisher","first-page":"e010403","DOI":"10.1136\/jitc-2024-010403","volume":"13","author":"Y Xu","year":"2025","unstructured":"Xu Y, Ding L, Wu M, Wang X, Wang L, Xu Z, et al. Lipid metabolic remodeling delays senescence of T cells to potentiate their immunity against solid tumors. J Immunother Cancer. 2025;13(1):e010403. https:\/\/doi.org\/10.1136\/jitc-2024-010403.","journal-title":"J Immunother Cancer"},{"key":"4383_CR29","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1016\/j.ccell.2023.04.016","volume":"41","author":"C Yan","year":"2023","unstructured":"Yan C, Zheng L, Jiang S, Yang H, Guo J, Jiang LY, et al. Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity. Cancer Cell. 2023;41:1276\u201393. https:\/\/doi.org\/10.1016\/j.ccell.2023.04.016.","journal-title":"Cancer Cell"},{"key":"4383_CR30","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1158\/2159-8290.CD-20-1243","volume":"11","author":"D Wang","year":"2021","unstructured":"Wang D, Prager BC, Gimple RC, Aguilar B, Alizadeh D, Tang H, et al. CRISPR screening of CAR T cells and cancer stem cells reveals critical dependencies for cell-based therapies. Cancer Discov. 2021;11:1192\u2013211. https:\/\/doi.org\/10.1158\/2159-8290.CD-20-1243.","journal-title":"Cancer Discov"},{"key":"4383_CR31","doi-asserted-by":"publisher","first-page":"4641","DOI":"10.1172\/JCI69489","volume":"123","author":"R Jabeen","year":"2013","unstructured":"Jabeen R, Goswami R, Awe O, Kulkarni A, Nguyen ET, Attenasio A, et al. Th9 cell development requires a BATF-regulated transcriptional network. J Clin Invest. 2013;123:4641\u201353. https:\/\/doi.org\/10.1172\/JCI69489.","journal-title":"J Clin Invest"},{"key":"4383_CR32","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/nature08114","volume":"460","author":"BU Schraml","year":"2009","unstructured":"Schraml BU, Hildner K, Ise W, Lee WL, Smith WA, Solomon B, et al. The AP-1 transcription factor Batf controls T(H)17 differentiation. Nat. 2009;460:405\u20139. https:\/\/doi.org\/10.1038\/nature08114.","journal-title":"Nat"},{"key":"4383_CR33","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1084\/jem.20091548","volume":"207","author":"BC Betz","year":"2010","unstructured":"Betz BC, Jordan-Williams KL, Wang C, Kang SG, Liao J, Logan MR, et al. Batf coordinates multiple aspects of B and T cell function required for normal antibody responses. J Exp Med. 2010;207:933\u201342. https:\/\/doi.org\/10.1084\/jem.20091548.","journal-title":"J Exp Med"},{"key":"4383_CR34","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1038\/s41586-019-1821-z","volume":"576","author":"J Wei","year":"2019","unstructured":"Wei J, Long L, Zheng W, Dhungana Y, Lim SA, Guy C, et al. Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy. Nat. 2019;576:471\u20136. https:\/\/doi.org\/10.1038\/s41586-019-1821-z.","journal-title":"Nat"},{"key":"4383_CR35","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1038\/nm.2232","volume":"16","author":"M Quigley","year":"2010","unstructured":"Quigley M, Pereyra F, Nilsson B, Porichis F, Fonseca C, Eichbaum Q, et al. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat Med. 2010;16:1147\u201351. https:\/\/doi.org\/10.1038\/nm.2232.","journal-title":"Nat Med"},{"key":"4383_CR36","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.canlet.2019.01.017","volume":"447","author":"M Chen","year":"2019","unstructured":"Chen M, Mao A, Xu M, Weng Q, Mao J, Ji J. CRISPR-Cas9 for cancer therapy: opportunities and challenges. Cancer Lett. 2019;447:48\u201355. https:\/\/doi.org\/10.1016\/j.canlet.2019.01.017.","journal-title":"Cancer Lett"},{"key":"4383_CR37","doi-asserted-by":"publisher","first-page":"4481","DOI":"10.7150\/thno.98574","volume":"14","author":"K Lei","year":"2024","unstructured":"Lei K, Li J, Tu Z, Gong C, Liu J, Luo M, et al. Endosome-microautophagy targeting chimera (eMIATAC) for targeted proteins degradation and enhance CAR-T cell anti-tumor therapy. Theranostics. 2024;14:4481\u201398. https:\/\/doi.org\/10.7150\/thno.98574.","journal-title":"Theranostics"},{"key":"4383_CR38","doi-asserted-by":"publisher","first-page":"1407","DOI":"10.1016\/j.ccell.2022.09.013","volume":"40","author":"X Zhang","year":"2022","unstructured":"Zhang X, Zhang C, Qiao M, Cheng C, Tang N, Lu S, et al. Depletion of BATF in CAR-T cells enhances antitumor activity by inducing resistance against exhaustion and formation of central memory cells. Cancer Cell. 2022;40:1407\u201322. https:\/\/doi.org\/10.1016\/j.ccell.2022.09.013.","journal-title":"Cancer Cell"},{"key":"4383_CR39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04004-2","volume":"9","author":"V Klepsch","year":"2018","unstructured":"Klepsch V, Hermann-Kleiter N, Do-Dinh P, Jakic B, Offermann A, Efremova M, et al. Nuclear receptor NR2F6 inhibition potentiates responses to PD-L1\/PD-1 cancer immune checkpoint blockade. Nat Commun. 2018;9:1538. https:\/\/doi.org\/10.1038\/s41467-018-04004-2.","journal-title":"Nat Commun"},{"key":"4383_CR40","doi-asserted-by":"publisher","first-page":"3009","DOI":"10.1158\/0008-5472.CAN-09-4076","volume":"70","author":"K Venuprasad","year":"2010","unstructured":"Venuprasad K. Cbl-b and itch: key regulators of peripheral T-cell tolerance. Cancer Res. 2010;70:3009\u201312. https:\/\/doi.org\/10.1158\/0008-5472.CAN-09-4076.","journal-title":"Cancer Res"},{"issue":"1","key":"4383_CR41","doi-asserted-by":"publisher","first-page":"e001688","DOI":"10.1136\/jitc-2020-001688","volume":"9","author":"J Kumar","year":"2021","unstructured":"Kumar J, Kumar R, Kumar Singh A, Tsakem EL, Kathania M, Riese MJ, et al. Deletion of Cbl-b inhibits CD8(+) T-cell exhaustion and promotes CAR T-cell function. J Immunother Cancer. 2021;9(1):e001688. https:\/\/doi.org\/10.1136\/jitc-2020-001688.","journal-title":"J Immunother Cancer"},{"key":"4383_CR42","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1126\/science.aaf2807","volume":"354","author":"KE Pauken","year":"2016","unstructured":"Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J, Khan O, et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Sci. 2016;354:1160\u20135. https:\/\/doi.org\/10.1126\/science.aaf2807.","journal-title":"Sci"},{"key":"4383_CR43","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.cell.2017.06.007","volume":"170","author":"HE Ghoneim","year":"2017","unstructured":"Ghoneim HE, Fan Y, Moustaki A, Abdelsamed HA, Dash P, Dogra P, et al. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell. 2017;170:142\u201357. https:\/\/doi.org\/10.1016\/j.cell.2017.06.007.","journal-title":"Cell"},{"key":"4383_CR44","doi-asserted-by":"publisher","first-page":"eabh0272","DOI":"10.1126\/scitranslmed.abh0272","volume":"13","author":"B Prinzing","year":"2021","unstructured":"Prinzing B, Zebley CC, Petersen CT, Fan Y, Anido AA, Yi Z, et al. Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity. Sci Transl Med. 2021;13:eabh0272. https:\/\/doi.org\/10.1126\/scitranslmed.abh0272.","journal-title":"Sci Transl Med"},{"key":"4383_CR45","doi-asserted-by":"publisher","DOI":"10.1126\/science.abj4008","volume":"375","author":"R Schmidt","year":"2022","unstructured":"Schmidt R, Steinhart Z, Layeghi M, Freimer JW, Bueno R, Nguyen VQ, et al. CRISPR activation and interference screens decode stimulation responses in primary human T cells. Sci. 2022;375:eabj4008. https:\/\/doi.org\/10.1126\/science.abj4008.","journal-title":"Sci"},{"key":"4383_CR46","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01915-z","volume":"9","author":"RC Schelker","year":"2024","unstructured":"Schelker RC, Fioravanti J, Mastrogiovanni F, Baldwin JG, Rana N, Li P, et al. LIM-domain-only 4 (LMO4) enhances CD8(+) T-cell stemness and tumor rejection by boosting IL-21-STAT3 signaling. Signal Transduct Target Ther. 2024;9:199. https:\/\/doi.org\/10.1038\/s41392-024-01915-z.","journal-title":"Signal Transduct Target Ther"},{"key":"4383_CR47","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1158\/2326-6066.CIR-20-0280","volume":"9","author":"J Wagner","year":"2021","unstructured":"Wagner J, Wickman E, Shaw TI, Anido AA, Langfitt D, Zhang J, et al. Antitumor effects of CAR T cells redirected to the EDB splice variant of fibronectin. Cancer Immunol Res. 2021;9:279\u201390. https:\/\/doi.org\/10.1158\/2326-6066.CIR-20-0280.","journal-title":"Cancer Immunol Res"},{"key":"4383_CR48","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-007199","author":"Z Zhang","year":"2023","unstructured":"Zhang Z, Liu C, Wang M, Sun R, Yang Z, Hua Z, et al. Treating solid tumors with TCR-based chimeric antigen receptor targeting extra domain B-containing fibronectin. J Immunother Cancer. 2023. https:\/\/doi.org\/10.1136\/jitc-2023-007199.","journal-title":"J Immunother Cancer"},{"key":"4383_CR49","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/s41423-023-01120-y","volume":"21","author":"S Liang","year":"2024","unstructured":"Liang S, Zheng R, Zuo B, Li J, Wang Y, Han Y, et al. SMAD7 expression in CAR-T cells improves persistence and safety for solid tumors. Cell Mol Immunol. 2024;21:213\u201326. https:\/\/doi.org\/10.1038\/s41423-023-01120-y.","journal-title":"Cell Mol Immunol"},{"key":"4383_CR50","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1515\/cmble-2015-0035","volume":"20","author":"H Wang","year":"2015","unstructured":"Wang H, Cai KY, Li W, Huang H. Sphingosine-1-Phosphate induces the migration and angiogenesis of Epcs through the Akt signaling pathway via Sphingosine-1-Phosphate Receptor 3\/Platelet-Derived Growth Factor Receptor-beta. Cell Mol Biol Lett. 2015;20:597\u2013611. https:\/\/doi.org\/10.1515\/cmble-2015-0035.","journal-title":"Cell Mol Biol Lett"},{"key":"4383_CR51","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2016.00218","volume":"6","author":"YI Rodriguez","year":"2016","unstructured":"Rodriguez YI, Campos LE, Castro MG, Aladhami A, Oskeritzian CA, Alvarez SE. Sphingosine-1 Phosphate: a new modulator of immune plasticity in the tumor microenvironment. Front Oncol. 2016;6:218. https:\/\/doi.org\/10.3389\/fonc.2016.00218.","journal-title":"Front Oncol"},{"key":"4383_CR52","doi-asserted-by":"publisher","first-page":"3671","DOI":"10.1111\/cas.13802","volume":"109","author":"M Nagahashi","year":"2018","unstructured":"Nagahashi M, Abe M, Sakimura K, Takabe K, Wakai T. The role of sphingosine-1-phosphate in inflammation and cancer progression. Cancer Sci. 2018;109:3671\u20138. https:\/\/doi.org\/10.1111\/cas.13802.","journal-title":"Cancer Sci"},{"key":"4383_CR53","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-006343","author":"G Gao","year":"2023","unstructured":"Gao G, Liao W, Shu P, Ma Q, He X, Zhang B, et al. Targeting sphingosine 1-phosphate receptor 3 inhibits T-cell exhaustion and regulates recruitment of proinflammatory macrophages to improve antitumor efficacy of CAR-T cells against solid tumor. J Immunother Cancer. 2023. https:\/\/doi.org\/10.1136\/jitc-2022-006343.","journal-title":"J Immunother Cancer"},{"key":"4383_CR54","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.629722","volume":"11","author":"SI Kim","year":"2020","unstructured":"Kim SI, Cassella CR, Byrne KT. Tumor burden and immunotherapy: impact on immune infiltration and therapeutic outcomes. Front Immunol. 2020;11:629722. https:\/\/doi.org\/10.3389\/fimmu.2020.629722.","journal-title":"Front Immunol"},{"key":"4383_CR55","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1016\/j.celrep.2018.06.040","volume":"24","author":"A Nguyen","year":"2018","unstructured":"Nguyen A, Ho L, Workenhe ST, Chen L, Samson J, Walsh SR, et al. HDACi delivery reprograms tumor-infiltrating myeloid cells to eliminate antigen-loss variants. Cell Rep. 2018;24:642\u201354. https:\/\/doi.org\/10.1016\/j.celrep.2018.06.040.","journal-title":"Cell Rep"},{"key":"4383_CR56","doi-asserted-by":"publisher","first-page":"4289","DOI":"10.1158\/1078-0432.CCR-22-2181","volume":"29","author":"A Nguyen","year":"2023","unstructured":"Nguyen A, Brown D, Krishnan R, Bastin D, Deng L, Chen L, et al. HDACi-dependent microenvironmental normalization overcomes tumor burden-induced T-cell exhaustion. Clin Cancer Res. 2023;29:4289\u2013305. https:\/\/doi.org\/10.1158\/1078-0432.CCR-22-2181.","journal-title":"Clin Cancer Res"},{"key":"4383_CR57","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1038\/s41590-021-00940-2","volume":"22","author":"Y Guo","year":"2021","unstructured":"Guo Y, Xie YQ, Gao M, Zhao Y, Franco F, Wenes M, et al. Metabolic reprogramming of terminally exhausted CD8(+) T cells by IL-10 enhances anti-tumor immunity. Nat Immunol. 2021;22:746\u201356. https:\/\/doi.org\/10.1038\/s41590-021-00940-2.","journal-title":"Nat Immunol"},{"key":"4383_CR58","doi-asserted-by":"publisher","first-page":"1693","DOI":"10.1038\/s41587-023-02060-8","volume":"42","author":"Y Zhao","year":"2024","unstructured":"Zhao Y, Chen J, Andreatta M, Feng B, Xie YQ, Wenes M, et al. IL-10-expressing CAR T cells resist dysfunction and mediate durable clearance of solid tumors and metastases. Nat Biotechnol. 2024;42:1693\u2013704. https:\/\/doi.org\/10.1038\/s41587-023-02060-8.","journal-title":"Nat Biotechnol"},{"key":"4383_CR59","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00128","volume":"10","author":"M Martinez","year":"2019","unstructured":"Martinez M, Moon EK. CAR T cells for solid tumors: new strategies for finding, infiltrating, and surviving in the tumor microenvironment. Front Immunol. 2019;10:128. https:\/\/doi.org\/10.3389\/fimmu.2019.00128.","journal-title":"Front Immunol"}],"container-title":["Clinical and Translational Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12094-026-04383-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12094-026-04383-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12094-026-04383-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T10:41:38Z","timestamp":1790160098000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12094-026-04383-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,7]]},"references-count":59,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["4383"],"URL":"https:\/\/doi.org\/10.1007\/s12094-026-04383-9","relation":{},"ISSN":["1699-3055"],"issn-type":[{"value":"1699-3055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,7]]},"assertion":[{"value":"27 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests relevant to the content of this article.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This article does not contain any studies involving human participants or animals performed by any of the authors.","order":2,"name":"Ethics","label":"Research involving human participants and\/or animals","group":{"name":"EthicsHeading","label":"Declarations"}}]}}