{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:06:44Z","timestamp":1792789604500,"version":"4.5.0"},"reference-count":196,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018904","name":"Beijing Xisike Clinical Oncology Research Foundation","doi-asserted-by":"publisher","award":["\u674e\u589e\u519b"],"award-info":[{"award-number":["\u674e\u589e\u519b"]}],"id":[{"id":"10.13039\/100018904","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Chimeric antigen receptor T-cell (CAR-T) therapy represents a revolutionary immunotherapy modality that has fundamentally transformed treatment paradigms for relapsed\/refractory (r\/r) hematological malignancies. For patients with r\/r diffuse large B-cell lymphoma (DLBCL), CD19-targeted CAR-T cell therapy is currently approved in second-line and post-second-line settings, achieving substantial clinical responses in selected B-cell leukemia\/lymphoma subgroups. Nevertheless, a significant proportion of B-cell lymphoma patients exhibit primary resistance or unsatisfactory long-term disease control after CAR-T infusion, substantially constraining therapeutic utility across both hematological and solid malignancies. Beyond the well-documented phenomenon of target antigen (CD19) loss, multifaceted resistance mechanisms against CAR-T therapy have been increasingly recognized. This review comprehensively explores potential resistance mechanisms in DLBCL through mechanistic insights from four interconnected dimensions: molecular alterations underlying tumor-associated CD19 expression loss; cell-intrinsic factors driving CAR-T cell differentiation arrest and functional exhaustion; immunomodulatory escape programs within the tumor microenvironment; and innate tumor cell resistance pathways. Elucidating these determinants provides critical foundations for developing novel therapeutic targets to overcome resistance. This knowledge promises to guide rational engineering of next-generation CAR-T cells with enhanced anti-tumor potency and reduced toxicity profiles, ultimately improving clinical outcomes across diverse malignancies.<\/jats:p>","DOI":"10.3389\/fonc.2026.1696105","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T05:23:42Z","timestamp":1771478622000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Research progress on resistance mechanisms to CAR-T cell therapy in diffuse large B-cell 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