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

ABSTRACT: 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 cMYC-driven metabolic reprogramming. Importantly, arginine enhanced 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE346776 | GEO | 2026/09/14

REPOSITORIES: GEO

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