Research progress on resistance mechanisms to CAR-T cell therapy in diffuse large B-cell lymphoma.

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.