Arginine Rewires eIF4F Translation Initiation to Overcome Fever-Induced CAR T-Cell Dysfunction

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 cMYC-driven metabolic reprogramming.