REVIEW article
Front. Oncol.
Sec. Pharmacology of Anti-Cancer Drugs
This article is part of the Research TopicNovel Targets and Therapeutic Strategies for Overcoming Drug Resistance in Hematologic MalignanciesView all 8 articles
Research Progress on Resistance Mechanisms to CAR-T Cell Therapy in Diffuse Large B-cell Lymphoma
Provisionally accepted
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Ji nan, China
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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.
Keywords: CAR (chimeric antigen receptor) T cell therapy2, DLBCL - Diffuse large B cell lymphoma, Immune Evasion, Molecular targeted drug, Resistance mechanism, Tumor microenvironment (TME)
Received: 31 Aug 2025; Accepted: 29 Jan 2026.
Copyright: © 2026 zhang, Li and liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Zengjun Li
jiye liu
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