Mechanisms underlying resistance to CAR-T cell therapy and strategies for enhancement

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a revolutionary approach in the treatment of hematological malignancies, including acute lymphoblastic leukemia, B-cell lymphoma, and multiple myeloma. Despite its promise, the clinical efficacy is often hampered by transient efficacy and subsequent relapse, which curtail the long-term success of this treatment. Current research focuses on overcoming these obstacles by exploring multitarget strategies and optimizing CAR-T cell design. This review summarizes recent insights into the resistance mechanisms associated with CAR-T cell therapy, and delineates emerging strategies for optimized CAR construction, including targeting multiple antigens, improving CAR design, and enhancing T-cell persistence. The goal is to provide a comprehensive overview of the field's current landscape to guide future research and the clinical application of CAR-T cell therapies.