{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T12:15:53Z","timestamp":1783512953880,"version":"3.55.0"},"reference-count":117,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006407","name":"Natural Science Foundation of Henan Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017700","name":"Henan Provincial Science and Technology Research Project","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100017700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape for relapsed\/refractory (R\/R) B-cell malignancies, including B-cell non-Hodgkin lymphoma (B-NHL), B-cell acute lymphoblastic leukemia (B-ALL), and related diseases. However, treatment failure caused by primary or secondary resistance remains a major clinical challenge, thereby limiting long-term efficacy and patient survival. Recent studies have systematically clarified the multidimensional mechanisms underlying resistance to CAR T-cell therapy, which can be broadly classified into tumor-intrinsic factors, CAR T-cell dysfunction, and an immunosuppressive tumor microenvironment (TME). At the same time, innovative strategies to overcome these barriers have rapidly emerged, including multitarget CAR design, metabolic and epigenetic modulation, and microenvironment remodeling. This review summarizes the latest advances in the mechanisms of resistance to CAR T-cell therapy and corresponding therapeutic strategies in B-cell malignancies, and further discusses future perspectives to provide a theoretical basis for optimizing CAR T-cell therapy.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1861111","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T05:46:59Z","timestamp":1781156819000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Resistance mechanisms and overcoming strategies for CAR T-cell therapy in B-cell hematologic malignancies"],"prefix":"10.3389","volume":"17","author":[{"given":"Pupu","family":"Li","sequence":"first","affiliation":[{"name":"Zhengzhou Key Laboratory of Lipid Metabolism and Precision Diagnosis & Treatment in Oncology, Oncology Department, The Fifth Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]},{"name":"State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Xue","sequence":"additional","affiliation":[{"name":"Zhengzhou Key Laboratory of Lipid Metabolism and Precision Diagnosis & Treatment in Oncology, Oncology Department, The Fifth Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]},{"name":"State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zisen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Zhengzhou Key Laboratory of Lipid Metabolism and Precision Diagnosis & Treatment in Oncology, Oncology Department, The Fifth Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]},{"name":"State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1186\/s13045-024-01633-7","article-title":"In vivo gene editing and in situ generation of chimeric antigen receptor cells for next-generation cancer immunotherapy","volume":"17","author":"Weiyue","year":"2024"},{"key":"B2","doi-asserted-by":"publisher","first-page":"4737","DOI":"10.1101\/2023.01.06.522784","article-title":"Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting","volume":"14","author":"Lee","year":"2023"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.7150\/jca.48976","article-title":"Current progress in CAR-T cell therapy for hematological Malignancies","volume":"12","author":"Han","year":"2021","journal-title":"J Cancer"},{"key":"B4","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1038\/s41392-025-02269-w","article-title":"CAR-T cell therapy for cancer: current challenges and future directions","volume":"10","author":"In\u00e9s","year":"2025"},{"key":"B5","doi-asserted-by":"publisher","first-page":"eadf1426","DOI":"10.1126\/sciimmunol.adf1426","article-title":"CD19 CAR antigen engagement mechanisms and affinity tuning","volume":"8","author":"Changhao","year":"2023"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-024-02392-7","article-title":"Third-generation anti-CD19 CAR T cells for relapsed\/refractory chronic lymphocytic leukemia: a phase 1\/2 study","volume":"38","author":"Patrick","year":"2024"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2023.09.021","article-title":"Arming CAR-T cells with cytokines and more: innovations in the fourth-generation CAR-T development","volume":"31","author":"Lin","year":"2023"},{"key":"B8","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s12943-022-01711-9","article-title":"Safety and antitumor activity of GD2-specific 4SCAR-T cells in patients with glioblastoma","volume":"22","author":"Zhuohao","year":"2023"},{"key":"B9","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1186\/s12943-023-01830-x","article-title":"Target delivery of a PD-1-TREM2 scFv by CAR-T cells enhances anti-tumor efficacy in colorectal cancer","volume":"22","author":"Jian","year":"2023"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.11.008","article-title":"Inhibiting intracellular CD28 in cancer cells enhances antitumor immunity and overcomes anti-PD-1 resistance via targeting PD-L1","volume":"43","author":"Zhen","year":"2024"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019004500","article-title":"Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity","volume":"136","author":"Fultang","year":"2020","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","first-page":"927153","DOI":"10.3389\/fimmu.2022.927153","article-title":"CAR-T cell therapy in hematological Malignancies: current opportunities and challenges","volume":"13","author":"Xiaomin","year":"2022"},{"key":"B13","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1111\/imr.12243","article-title":"Going viral: chimeric antigen receptor T-cell therapy for hematological Malignancies","volume":"263","author":"Gill","year":"2015"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1709866","article-title":"Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia","volume":"378","author":"Maude","year":"2018"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1707447","article-title":"Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma","volume":"377","author":"Sattva","year":"2017"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1914347","article-title":"KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma","volume":"382","author":"Michael","year":"2020"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(20)31366-0","article-title":"Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study","volume":"396","author":"Jeremy","year":"2020"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2406526","article-title":"Obecabtagene autoleucel in adults with B-cell acute lymphoblastic leukemia","volume":"391","author":"Roddie","year":"2024","journal-title":"N Engl J Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2024850","article-title":"Idecabtagene vicleucel in relapsed and refractory multiple myeloma","volume":"384","author":"Nikhil","year":"2021"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(21)00933-8","article-title":"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","volume":"398","author":"Jesus","year":"2021"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(21)00375-2","article-title":"Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study","volume":"22","author":"Stephen","year":"2021"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(18)30864-7","article-title":"Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial","volume":"20","author":"Frederick","year":"2018"},{"key":"B23","doi-asserted-by":"publisher","first-page":"13332","DOI":"10.3390\/ijms232113332","article-title":"Chimeric antigen receptor T-cell therapy: what we expect soon","volume":"23","author":"Massimo","year":"2022"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1200\/jco.21.02370","article-title":"Three-year follow-up of KTE-X19 in patients with relapsed\/refractory mantle cell lymphoma, including high-risk subgroups, in the ZUMA-2 study","volume":"41","author":"Michael","year":"2022"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(21)00591-x","article-title":"Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial","volume":"23","author":"Caron","year":"2021"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020009098","article-title":"KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed\/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results","volume":"138","author":"Bijal","year":"2021"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2024027460","article-title":"ZUMA-8: a phase 1 study of brexucabtagene autoleucel in patients with relapsed\/refractory chronic lymphocytic leukemia","volume":"146","author":"Davids","year":"2025"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0985-x","article-title":"NR4A transcription factors limit CAR T cell function in solid tumours","volume":"567","author":"Joyce","year":"2019"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2116133","article-title":"Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma","volume":"386","author":"Frederick","year":"2021"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01731-4","article-title":"Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial","volume":"28","author":"Sattva","year":"2022"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01622-0","article-title":"Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial","volume":"28","author":"Fowler","year":"2022"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/s2352-3026(21)00238-6","article-title":"CD19-targeted chimeric antigen receptor T-cell therapy for CNS relapsed or refractory acute lymphocytic leukaemia: a post-hoc analysis of pooled data from five clinical trials","volume":"8","author":"Allison Barz","year":"2021"},{"key":"B33","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1186\/s12943-023-01886-9","article-title":"Safety and efficacy of a novel anti-CD19 chimeric antigen receptor T cell product targeting a membrane-proximal domain of CD19 with fast on- and off-rates against non-Hodgkin lymphoma: a first-in-human study","volume":"22","author":"Yunlin","year":"2023"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00807-1","article-title":"Mechanisms of resistance to chimeric antigen receptor-T cells in haematological Malignancies","volume":"22","author":"Marco","year":"2023"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2025.04.002","article-title":"Mechanisms underlying resistance to CAR-T cell therapy and strategies for enhancement","volume":"83","author":"Anran","year":"2025"},{"key":"B36","doi-asserted-by":"publisher","first-page":"e2203106","DOI":"10.1002\/advs.202203106","article-title":"Intraparticle double-scattering-decoded sonogenetics for augmenting immune checkpoint blockade and CAR-T therapy","volume":"9","author":"Duo","year":"2022"},{"key":"B37","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1186\/s13045-025-01744-9","article-title":"Challenges and limitations of chimeric antigen receptor T-cell therapies in solid tumors: why are approvals restricted to hematologic Malignancies","volume":"18","author":"Manh-Cuong","year":"2025"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41570-025-00768-6","article-title":"Small-molecule control of CAR T cells","volume":"9","author":"Eric","year":"2025"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2021.1894648","article-title":"Resistance to CART cell therapy: lessons learned from the treatment of hematological Malignancies","volume":"62","author":"Sakemura","year":"2021","journal-title":"Leuk Lymphoma"},{"key":"B40","doi-asserted-by":"publisher","first-page":"18","DOI":"10.20517\/cdr.2023.100","article-title":"Advancing CAR T-cell therapy for chronic lymphocytic leukemia: exploring resistance mechanisms and the innovative strategies to overcome them","volume":"7","author":"Azra","year":"2024"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01956","article-title":"Differences in expansion potential of naive chimeric antigen receptor T cells from healthy donors and untreated chronic lymphocytic leukemia patients","volume":"8","author":"Hoffmann","year":"2017","journal-title":"Front Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.hoc.2013.01.003","article-title":"Understanding the immunodeficiency in chronic lymphocytic leukemia: potential clinical implications","volume":"27","author":"Riches","year":"2013","journal-title":"Hematol Oncol Clin North Am"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1407222","article-title":"Chimeric antigen receptor T cells for sustained remissions in leukemia","volume":"371","author":"Maude","year":"2014","journal-title":"N Engl J Med"},{"key":"B44","doi-asserted-by":"publisher","first-page":"303ra139","DOI":"10.1126\/scitranslmed.aac5415","article-title":"Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia","volume":"7","author":"Porter","year":"2015","journal-title":"Sci Transl Med"},{"key":"B45","doi-asserted-by":"publisher","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":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2021.02.010","article-title":"Mechanisms of response and resistance to CAR T cell therapies","volume":"69","author":"Trisha","year":"2021"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-02-769208","article-title":"Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults","volume":"129","author":"Gardner","year":"2017","journal-title":"Blood"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05707-3","article-title":"CAR immune cells: design principles, resistance and the next generation","volume":"614","author":"Louai","year":"2023"},{"key":"B49","doi-asserted-by":"publisher","first-page":"115973","DOI":"10.1016\/j.celrep.2025.115973","article-title":"CAR-T cells containing CD28 versus 4-1BB co-stimulatory domains show distinct metabolic profiles in patients","volume":"44","author":"Molly","year":"2025"},{"key":"B50","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":"Evan","year":"2021"},{"key":"B51","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":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(21)01206-x","article-title":"Immune checkpoint inhibitors in melanoma","volume":"398","author":"Carlino","year":"2021","journal-title":"Lancet"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2014.56.2025","article-title":"Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell Malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor","volume":"33","author":"Kochenderfer","year":"2015","journal-title":"J Clin Oncol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-06-741033","article-title":"CTLA-4: a moving target in immunotherapy","volume":"131","author":"Behzad","year":"2017"},{"key":"B55","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1056\/nejmoa1804980","article-title":"Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma","volume":"380","author":"Schuster","year":"2019","journal-title":"N Engl J Med"},{"key":"B56","doi-asserted-by":"publisher","first-page":"5010","DOI":"10.3390\/ijms20205010","article-title":"Resistance mechanisms to CAR T-cell therapy and overcoming strategy in B-cell hematologic Malignancies","volume":"20","author":"Song","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.cd-19-0813","article-title":"Impaired death receptor signaling in leukemia causes antigen-independent resistance by inducing CAR T-cell dysfunction","volume":"10","author":"Singh","year":"2020","journal-title":"Cancer Discov"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021014304","article-title":"Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic Malignancies","volume":"140","author":"T","year":"2022"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27740","article-title":"Cancer stem cells (CSCs) in cancer progression and therapy","volume":"234","author":"Najafi","year":"2019","journal-title":"J Cell Physiol"},{"key":"B60","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1038\/s41392-020-00430-1","article-title":"Targeting cancer stem cells for reversing therapy resistance: mechanism, signaling, and prospective agents","volume":"6","author":"Zhou","year":"2021","journal-title":"Signal Transduct Target Ther"},{"key":"B61","doi-asserted-by":"publisher","first-page":"101421","DOI":"10.1016\/j.omtm.2025.101421","article-title":"Capivasertib enhances chimeric antigen receptor T cell activity in preclinical models of B cell lymphoma","volume":"33","author":"Hsieh","year":"2025"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1709919","article-title":"Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia","volume":"378","author":"Park","year":"2018","journal-title":"N Engl J Med"},{"key":"B63","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/s1470-2045(18)30864-7","article-title":"Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial","volume":"20","author":"Locke","year":"2019","journal-title":"Lancet Oncol"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-05-718395","article-title":"Resistance to anti-CD19\/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking","volume":"129","author":"Braig","year":"2017","journal-title":"Blood"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.cd-15-1020","article-title":"Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy","volume":"5","author":"Sotillo","year":"2015","journal-title":"Cancer Discov"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1097\/cji.0000000000000169","article-title":"CD19 isoforms enabling resistance to CART-19 immunotherapy are expressed in B-ALL patients at initial diagnosis","volume":"40","author":"Fischer","year":"2017","journal-title":"J Immunother"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.00383-18","article-title":"CD19 alterations emerging after CD19-directed immunotherapy cause retention of the misfolded protein in the endoplasmic reticulum","volume":"38","author":"Bagashev","year":"2018","journal-title":"Mol Cell Biol"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-08-665547","article-title":"Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy","volume":"127","author":"Gardner","year":"2016","journal-title":"Blood"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12320","article-title":"CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity","volume":"7","author":"Jacoby","year":"2016","journal-title":"Nat Commun"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25235","article-title":"Heterogeneity of surface CD19 and CD22 expression in B lymphoblastic leukemia","volume":"93","author":"Rosenthal","year":"2018","journal-title":"Am J Hematol"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0146-z","article-title":"Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia","volume":"24","author":"Orlando","year":"2018","journal-title":"Nat Med"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0201-9","article-title":"Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell","volume":"24","author":"Ruella","year":"2018","journal-title":"Nat Med"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4441","article-title":"CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy","volume":"24","author":"Fry","year":"2018","journal-title":"Nat Med"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1054-1","article-title":"CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape","volume":"568","author":"Hamieh","year":"2019","journal-title":"Nature"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.618387","article-title":"Befriending the hostile tumor microenvironment in CAR T-cell therapy","volume":"11","author":"Lindo","year":"2020","journal-title":"Front Immunol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v128.22.43.43","article-title":"Overcoming the immunosuppressive tumor microenvironment of Hodgkin lymphoma using chimeric antigen receptor T cells","volume":"7","author":"Ruella","year":"2017","journal-title":"Cancer Discov"},{"key":"B77","doi-asserted-by":"publisher","first-page":"6995","DOI":"10.1158\/1078-0432.ccr-19-0101","article-title":"Clinical efficacy and tumor microenvironment influence in a dose-escalation study of anti-CD19 chimeric antigen receptor T cells in refractory B-cell non-Hodgkin's lymphoma","volume":"25","author":"Yan","year":"2019","journal-title":"Clin Cancer Res"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-015-1692-6","article-title":"Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T","volume":"64","author":"Burga","year":"2015","journal-title":"Cancer Immunol Immunother"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.cir-15-0230","article-title":"Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas","volume":"4","author":"Long","year":"2016","journal-title":"Cancer Immunol Res"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1038\/cti.2017.43","article-title":"Regulatory T-cell heterogeneity and the cancer immune response","volume":"6","author":"Ward-Hartstonge","year":"2017","journal-title":"Clin Transl Immunol"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2017.41","article-title":"Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody blinatumomab in patients with B-precursor ALL","volume":"31","author":"Duell","year":"2017","journal-title":"Leukemia"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021012811","article-title":"Targeting cancer-associated fibroblasts in the bone marrow prevents resistance to CART-cell therapy in multiple myeloma","volume":"139","author":"Sakemura","year":"2022","journal-title":"Blood"},{"key":"B83","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1186\/s12967-025-06276-x","article-title":"IDO1 inhibition enhances CLDN18.2-CAR-T cell therapy in gastrointestinal cancers by overcoming kynurenine-mediated metabolic suppression in the tumor microenvironment","volume":"23","author":"Zhaorong","year":"2025"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-01-621474","article-title":"Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs","volume":"125","author":"Ninomiya","year":"2015","journal-title":"Blood"},{"key":"B85","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.3390\/cells8091070","article-title":"Overcoming immunological resistance enhances the efficacy of a novel anti-tMUC1-CAR T cell treatment against pancreatic ductal adenocarcinoma","volume":"8","author":"Yazdanifar","year":"2019","journal-title":"Cells"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.cd-17-1033","article-title":"CD38-mediated immunosuppression as a mechanism of tumor cell escape from PD-1\/PD-L1 blockade","volume":"8","author":"Chen","year":"2018","journal-title":"Cancer Discov"},{"key":"B87","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40164-025-00732-6","article-title":"Hypoxia promotes BCMA loss and a suppressive secretome thereby hindering CAR T cell therapy in multiple myeloma","volume":"15","author":"Chenggong","year":"2026"},{"key":"B88","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1007\/s00262-025-04047-7","article-title":"Exosomal PD-L1 derived from hypoxia nasopharyngeal carcinoma cell exacerbates CD8(+) T cell suppression by promoting PD-L1 upregulation in macrophages","volume":"74","author":"Xiaofei","year":"2025"},{"key":"B89","doi-asserted-by":"publisher","first-page":"e2424251122","DOI":"10.1073\/pnas.2424251122","article-title":"Prostaglandin E(2)-EP2\/EP4 signaling induces the tumor-infiltrating Treg phenotype for tumor growth","volume":"122","author":"Ryuma","year":"2025"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1172\/jci87366","article-title":"Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies","volume":"126","author":"Ruella","year":"2016","journal-title":"J Clin Invest"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01436-0","article-title":"CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell Malignancies: a phase 1 trial","volume":"27","author":"Spiegel","year":"2021","journal-title":"Nat Med"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-020-00856-8","article-title":"Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia","volume":"13","author":"Dai","year":"2020","journal-title":"J Hematol Oncol"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1081-3","article-title":"Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell Malignancies: a phase 1 dose escalation and expansion trial","volume":"26","author":"Shah","year":"2020","journal-title":"Nat Med"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.3109\/10428194.2016.1161185","article-title":"Blinatumomab: a CD19\/CD3 bispecific T cell engager (BiTE) with unique anti-tumor efficacy","volume":"57","author":"Goebeler","year":"2016","journal-title":"Leuk Lymphoma"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1609783","article-title":"Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia","volume":"376","author":"Kantarjian","year":"2017","journal-title":"N Engl J Med"},{"key":"B96","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1016\/j.molcel.2020.05.018","article-title":"The molecular link from diet to cancer cell metabolism","volume":"80","author":"Bose","year":"2020","journal-title":"Mol Cell"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1172\/jci85309","article-title":"CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients","volume":"126","author":"Turtle","year":"2016","journal-title":"J Clin Invest"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.09.004","article-title":"Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells","volume":"28","author":"Zhao","year":"2015","journal-title":"Cancer Cell"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.01.021","article-title":"Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells","volume":"44","author":"Kawalekar","year":"2016","journal-title":"Immunity"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01326-5","article-title":"Antigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells","volume":"27","author":"Singh","year":"2021"},{"key":"B101","doi-asserted-by":"publisher","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":"B102","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501997","article-title":"TLR-mediated innate production of IFN-\u03b3 by CD8+ T cells is independent of glycolysis","volume":"196","author":"Fiamma","year":"2016"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2017.249","article-title":"Toll-like receptor 2 costimulation potentiates the antitumor efficacy of CAR T cells","volume":"32","author":"Lai","year":"2018","journal-title":"Leukemia"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-19-3417","article-title":"A humanized Lym-1 CAR with novel DAP10\/DAP12 signaling domains demonstrates reduced tonic signaling and increased antitumor activity in B-cell lymphoma models","volume":"26","author":"Zheng","year":"2020"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-01-552174","article-title":"Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15","volume":"123","author":"Xu","year":"2014","journal-title":"Blood"},{"key":"B106","article-title":"Fueling chimeric antigen receptor T cells with cytokines","volume":"10","author":"Jin","year":"2020","journal-title":"Am J Cancer Res"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.cd-17-0538","article-title":"Constitutive signaling from an engineered IL7 receptor promotes durable tumor elimination by tumor-redirected T cells","volume":"7","author":"Shum","year":"2017","journal-title":"Cancer Discov"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2010.75","article-title":"Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma\/leukemia effects and safety","volume":"24","author":"Hoyos","year":"2010","journal-title":"Leukemia"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.can-10-3843","article-title":"Reprogramming CD19-specific T cells with IL-21 signaling can improve adoptive immunotherapy of B-lineage Malignancies","volume":"71","author":"Singh","year":"2011","journal-title":"Cancer Res"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.04.051","article-title":"Engineered tumor-targeted T cells mediate enhanced anti-tumor efficacy both directly and through activation of the endogenous immune system","volume":"23","author":"Avanzi","year":"2018","journal-title":"Cell Rep"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-09-738245","article-title":"PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR","volume":"129","author":"Chong","year":"2017","journal-title":"Blood"},{"key":"B112","doi-asserted-by":"publisher","first-page":"eaba7365","DOI":"10.1126\/science.aba7365","article-title":"CRISPR-engineered T cells in patients with refractory cancer","volume":"367","author":"Stadtmauer","year":"2020","journal-title":"Science"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-018-2281-2","article-title":"CRISPR\/Cas9-mediated PD-1 disruption enhances human mesothelin-targeted CAR T cell effector functions","volume":"68","author":"Hu","year":"2019","journal-title":"Cancer Immunol Immunother"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4195","article-title":"Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo","volume":"36","author":"Rafiq","year":"2018","journal-title":"Nat Biotechnol"},{"key":"B115","doi-asserted-by":"publisher","first-page":"12201","DOI":"10.3390\/ijms252212201","article-title":"Significant advancements and evolutions in chimeric antigen receptor design","volume":"25","author":"Anna","year":"2024"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1172\/jci83092","article-title":"Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition","volume":"126","author":"Cherkassky","year":"2016","journal-title":"J Clin Invest"},{"key":"B117","doi-asserted-by":"publisher","first-page":"djv146","DOI":"10.1093\/jnci\/djv146","article-title":"Impact of a new fusion receptor on PD-1-mediated immunosuppression in adoptive T cell therapy","volume":"107","author":"Kobold","year":"2015","journal-title":"J Natl Cancer Inst"}],"updated-by":[{"DOI":"10.3389\/fimmu.2026.1907428","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000}}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1861111\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T11:31:22Z","timestamp":1783510282000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1861111\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,11]]},"references-count":117,"alternative-id":["10.3389\/fimmu.2026.1861111"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1861111","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,11]]},"article-number":"1861111"}}