Rewiring T Cell Metabolism to Enhance CAR T Cell Function in Solid Tumor Microenvironments.

Background/Objectives: Chimeric antigen receptor (CAR) T cells have shown remarkable clinical success in certain blood cancers but remain largely ineffective in solid tumors. A major reason for this limitation is the hostile tumor microenvironment, which restricts oxygen and nutrients while producing toxic metabolites that suppress immune cell activity. This review aims to examine how targeted metabolic reprogramming can overcome these barriers and improve CAR T cell performance. Methods: We evaluated preclinical and translational studies that focused on engineering CAR T cells to resist hypoxia, improve nutrient utilization, reduce metabolic exhaustion, and counteract suppressive metabolites in solid tumors. Results: Emerging strategies include engineering resistance to low oxygen and high lactate, enhancing nutrient uptake through transporter overexpression, and blocking inhibitory pathways such as those driven by adenosine. These approaches improve CAR T cell persistence, memory formation, and cytotoxic function in challenging tumor environments. Conclusions: Integrating metabolic reprogramming with conventional CAR design is essential to unlock the full potential of CAR T therapy against solid tumors. Continued innovation in this area will be critical for translating laboratory advances into effective clinical treatments.