Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of select hematologic malignancies, where disease accessibility, well-defined lineage antigens, and clinically manageable target cell depletion have enabled more durable responses. However, translation to solid tumors has been far more limited due to the structural, metabolic, and immunologic barriers that are less prominent in many blood cancers. This review uses hematologic malignancies as the standard for CAR T cell therapy success while synthesizing mechanistic insights from preclinical models and emerging data from early-phase solid tumor trials. We define how antigen heterogeneity, impaired trafficking, metabolic suppression, immunosuppressive signaling, and on-target, off-tumor toxicity limit CAR T cell infiltration, persistence, and function in solid tumors. We also highlight recurring clinical patterns indicating that antitumor activity is most achievable when tumor-enriched antigens are targeted, delivery strategies overcome physical barriers, and CAR T cells are engineered to resist exhaustion and suppression within hostile microenvironments. By evaluating next-generation approaches, including cytokine armoring, multi-antigen and logic-gated recognition, regional delivery, and regulatable safety circuits, we propose a model for rational CAR T cell design tailored to solid tumor biology while informed by the principles underlying hematologic success. These insights support context-dependent engineered immunotherapies capable of extending the durability and safety achieved in blood cancers to solid malignancies.
Liu et al. (2026) studied this question.