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

Sustained high-grade fever in a retrospective cohort of B cell acute lymphoblastic leukemia patients treated with CD22-directed CAR T cells is linked to an inverse clinical response.

• Why it matters: Fever, a hallmark of cytokine release syndrome, has been understudied as a modifier of CAR T therapeutic efficacy, leaving a gap in how to preserve function during CRS-associated hyperthermia.
• What they did: In experimental hyperthermia, CAR signaling, cytotoxicity, and metabolic fitness were impaired via dysregulated arginine metabolism; arginine supplementation restored function, requiring mTOR-dependent eIF4F recruitment and c-MYC-driven metabolic reprogramming.
• The result: Arginine enhanced GMP-manufactured CAR T cell function under normothermia and oral supplementation improved in vivo efficacy, identifying metabolic control of translation as a fever-sensitive checkpoint.