Arginine rewires eIF4F translation initiation to overcome fever-induced CAR T cell dysfunction

Chimeric antigen receptor (CAR) T cell therapy has revolutionized treatment of hematological malignancies, but cytokine release syndrome (CRS) remains a major toxicity. Fever-a hallmark of CRS-has been understudied as a modifier of therapeutic efficacy. In a retrospective cohort of patients with B cell acute lymphoblastic leukemia treated with CD22-directed CAR T cells (NCT02315612), sustained high-grade fever inversely correlated with clinical response. Mechanistically, experimental hyperthermia impaired proximal CAR signaling, reduced cytotoxicity, and compromised metabolic fitness through dysregulated arginine metabolism. Arginine supplementation restored CAR T cell function following hyperthermic stress and enhanced cytotoxicity under normothermic conditions. This effect required mTOR-dependent recruitment of the eIF4F translation-initiation complex and downstream c-MYC-driven metabolic reprogramming. Importantly, arginine enhanced good manufacturing practice (GMP)-manufactured CAR T cell function under normothermia, while oral supplementation improved in vivo efficacy. These findings identify metabolic control of translation as a fever-sensitive checkpoint and establish arginine supplementation as a tractable strategy to enhance CAR T cell efficacy.