GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE346nnn/GSE346776/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE346776GEOGSEfalseArginine Rewires eIF4F Translation Initiation to Overcome Fever-Induced CAR T-Cell DysfunctionChimeric 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.2026/09/14GSE346776GSM10040274GSM10040273GSM10040272GSM10040271GSM10040267GSM10040266GSM10040276GSM10040265GSM10040275GSM10040269GSM10040268GSM1004027030173346776Homo sapiens