Boosting CAR T cell efficacy in cancer with metabolic insights from design to diet

Chimeric antigen receptor (CAR) T cell therapy has advanced the treatment of haematological cancers, but faces challenges achieving durable responses, particularly in solid tumours. Metabolism is a major determinant of CAR T cell fitness, persistence and function. The choice of co-stimulatory domain induces distinct metabolic profiles within the CAR T cell, making it crucial to consider engineering approaches that favour T cell metabolic phenotypes conducive to sustained antitumour activity. Likewise, variations in manufacturing platforms and expansion conditions, including nutrient composition, lead to distinct metabolic and functional profiles, yet the metabolic parameters in manufacturing protocols for clinical studies remain largely unstandardized. Beyond intrinsic cellular engineering, host metabolism exerts a sizeable influence on therapeutic outcome. Diet-based interventions offer a clinically accessible and scalable way to modulate systemic metabolism, which may in turn enhance CAR T cell efficacy. In this Review, we examine how metabolism integrates with CAR design, cell production and host conditioning. We highlight opportunities to leverage diet as a promising, underexplored avenue towards overcoming current barriers in treating solid tumours with CAR T cell therapy. Integrating metabolic and dietary strategies may unlock the potential for durable, effective CAR T cell therapy.