Limitations of CAR-T-Cell Therapy in Hematologic Malignancies: Focusing on Antigen Escape and T-Cell Dysfunction

Chimeric antigen receptor T (CAR-T)-cell therapy has revolutionized the treatment of hematological malignancies, yet long-term efficacy remains constrained by antigen escape and T-cell dysfunction. Recent advances have rapidly elucidated the molecular underpinnings of antigen escape mechanisms and intrinsic T-cell dysfunction, revealing novel vulnerabilities in current CAR-T paradigms. In this review, we discuss the limitations of CAR-T-cell therapy in hematological malignancies, particularly regarding antigen escape mechanisms and T-cell dysfunction. It is noteworthy that in recent years, multi-targeted CAR-T and engineered CAR-T cells have demonstrated promising clinical efficacy in overcoming drug resistance and relapse in hematological malignancies. Here, we also discuss emerging approaches to enhance the efficacy of CAR-T-cell therapy, including advanced CAR-T-cell engineering techniques, the identification of novel therapeutic targets, and the development of multi-targeted CAR-T-cell strategies.