Navigating the frontier of CAR-T cell resistance: From underlying mechanisms to innovative therapeutic solutions.

Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in the treatment of relapsed or refractory hematological malignancies, particularly acute B-cell lymphoblastic leukemia (B-ALL), B-cell lymphoma (BCL), and multiple myeloma (MM). However, resistance in hematological malignancies and limited immune responses in solid tumors remain major challenges for CAR-T cell therapy. Tumor antigen loss or modulation, dysregulated apoptotic signaling, CAR-T cell-intrinsic dysfunction, and immunosuppressive components within the tumor microenvironment (TME) significantly compromise therapeutic outcomes. Therefore, understanding the mechanisms that mediate resistance to CAR-T cell therapy and exploring strategies to overcome therapeutic failure are crucial for optimizing clinical results. This review systematically elucidates the mechanisms underlying resistance to CAR-T cell therapy and discusses potential countermeasures, including dual-targeted approaches, innovative CAR engineering strategies, TME reprogramming, and combination immunotherapies.