CAR-T in solid tumors: Obstacles and potential strategies

Chimeric antigen receptor T (CAR-T) cell therapy has achieved remarkable success in treating hematologic malignancies, yet its efficacy in solid tumors remains constrained by multiple challenges. In this review, we summarize the main obstacles hindering CAR-T therapy in solid tumors, including suboptimal antigen targeting, poor trafficking and infiltration into tumor sites, and insufficient persistence of CAR-T cells. Furthermore, we discuss emerging strategies to overcome these hurdles, which can be categorized into two complementary aspects. The first focuses on optimizing intrinsic CAR-T properties for improved adaptation to the tumor microenvironment (TME), such as enriching less-differentiated T cell subsets, modifying CAR constructs, refining ex vivo culture conditions, and modulating specific genes or metabolic pathways through genetic or pharmacological interventions. The second approach aims to remodel the immunosuppressive TME by neutralizing inhibitory mediators, blocking immune checkpoints, and targeting immunosuppressive cell populations and stromal components. Importantly, we also summarized recent progress in in vivo CAR-T therapy. This review provides a comprehensive overview of the obstacles facing CAR-T in solid tumors, addressing both the underlying mechanisms and the translational potential of current and future strategies.