Metabolic reprogramming of CAR-T cells: a multi-pronged strategy to conquer the immunosuppressive tumor microenvironment

CAR-T cell therapy has demonstrated remarkable success in hematologic malignancies, yet its application in solid tumors continues to face formidable challenges posed by metabolic dysregulation within the tumor microenvironment (TME). The TME impairs CAR-T cell effector function and persistence through mechanisms such as nutrient deprivation (e.g., glucose scarcity), disrupted lipid metabolism, and the accumulation of immunosuppressive metabolites (e.g., kynurenine). This review systematically outlines multidimensional strategies to enhance CAR-T cell efficacy through metabolic reprogramming: in glucose metabolism, approaches such as ex vivo metabolic priming, genetic engineering, and pharmacological modulation improve glucose uptake and utilization; in lipid metabolism, domain selection, gene modification, and combinatorial interventions optimize fatty acid oxidation and memory phenotype maintenance; in amino acid metabolism, engineering and pharmacological inhibition alleviate essential amino acid depletion and metabolite-induced immunosuppression. Collectively, these strategies endow CAR-T cells with greater metabolic adaptability, laying the foundation for breakthroughs in tumor therapy. Looking ahead, multi-pathway synergistic interventions, dynamically controllable metabolic regulation, and personalized metabolic adaptation are poised to become central pillars in the development of next-generation CAR-T cells.