Unleashing CAR-T potential in solid tumors: overcoming intrinsic and extrinsic hurdles to improve therapy

Chimeric antigen receptor (CAR) T cell therapy has shown transformative success in hematologic malignancies, yet its application in solid tumors remains limited by a combination of intrinsic and extrinsic barriers. Intrinsically, CAR-T cells face challenges such as CAR instability, T cell exhaustion, insufficient tumor infiltration, and poor persistence. Extrinsically, the tumor microenvironment (TME) acts as a formidable obstacle, with physical barriers, metabolic constraints, and immunosuppressive signals that dampen CAR-T cell function. Recent advancements in CAR transduction, genetic reprogramming, and combination therapies have revealed novel strategies to overcome these hurdles. This review explores cutting-edge innovations aimed at unleashing the full potential of CAR-T therapy in solid tumors, focusing on strategies that enhance CAR-T cell function and persistence while addressing the immunosuppressive TME. By examining both intrinsic and extrinsic factors, we provide a comprehensive framework for future research and clinical application to improve CAR-T therapy for solid tumor treatment.