Metabolic reprogramming for CAR-T cell therapy: advances and perspectives

Chimeric antigen receptor T cell (CAR-T) therapy has redefined the therapeutic landscape of hematological malignancies, yet its efficacy in solid tumors remains constrained by rapid functional attrition. Metabolic fitness serves as the primary arbiter of CAR-T cell fate, orchestrating the transitions between quiescence, effector activation, and terminal exhaustion. Within the immunosuppressive tumor microenvironment (TME), CAR-T cells must navigate a hostile metabolic landscape defined by nutrient deprivation, hypoxia, and toxic metabolite accumulation. Overcoming these barriers necessitates a paradigm shift toward multifaceted metabolic engineering that synchronizes intrinsic CAR-T cell rewiring with the extrinsic modulation of TME-derived inhibitory signals. Here, we propose a unified model of CAR-T cell metabolic integration, evaluate emerging platforms for metabolic optimization, and sketch a vision for translating these bioengineering strategies into durable clinical remissions.