Resistance mechanisms and overcoming strategies for CAR T-cell therapy in B-cell hematologic malignancies

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.