Challenges and recent advances in CAR-T cell therapy for solid tumors

Chimeric Antigen Receptor T-cell (CAR-T) therapy has achieved revolutionary success in hematological malignancies. However, its broad application in solid tumor treatment still faces fundamental challenges. This review explores the multiple obstacles encountered by CAR-T therapy in conquering solid tumors, including core issues such as tumor antigen heterogeneity, the immunosuppressive tumor microenvironment (TME), difficulties in T-cell infiltration, and treatment-related toxicities. Beyond merely describing these challenges, this article focuses on organizing the breakthrough strategies that have emerged in recent years. It highlights several cutting-edge directions, including the discovery of novel targets (e.g., Claudin 18.2, B7-H3), innovative CAR designs (e.g., logic-gated CARs, armored CARs), local delivery and in situ generation techniques, and combination therapies (e.g., with radiotherapy, immune checkpoint inhibitors, oncolytic viruses). Finally, this review outlines future directions of developing intelligent, controllable next-generation CAR-T technologies through multidisciplinary integration, hoping to provide a valuable perspective for advancing basic research and clinical translation in this field.