Bioengineering CAR-T cells to function in hostile tumor microenvironments

Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematological malignancies but remains largely ineffective in solid tumors. Accumulating evidence indicates that this limitation reflects not only suboptimal antigen recognition but also the inability of therapeutic cells to reach and function within the suppressive tumor microenvironment. This review synthesizes recent advances in CAR-T cell bioengineering aimed at overcoming physical barriers, immunosuppressive signaling, metabolic stress, and cellular exhaustion that characterize solid tumors, which are a leading cause of cancer-related mortality worldwide. We highlight in vivo-validated strategies that enhance tumor trafficking, intratumoral retention, stress resilience, and resistance to immunosuppression, while delineating key translational challenges and safety considerations required for clinical translation.