Iron-mediated ferroptosis impairs CAR-T cell function and antitumor efficacy

Long-term persistence of chimeric antigen receptor (CAR)-T cells is essential for durable therapeutic efficacy but the mechanisms underlying CAR-T cell dysfunction remain unclear. On the basis of integrated analyses of clinical samples from participants with multiple myeloma and acute lymphoblastic leukemia treated with CAR-T cells, we show that rapid expansion of CAR-T cells after infusion is followed by a 'diminution' phase characterized by ferroptosis-associated features and elevated serum iron levels. In preclinical cancer models in female mice and ex vivo culture systems, excess intracellular iron impaired CAR-T cell function. Mechanistically, iron promoted ferroptosis by increasing mitochondrial reactive oxygen species and lipid peroxidation, in part through acyl-CoA synthetase long-chain family member 4 (ACSL4)-associated lipid remodeling. Targeting ferroptosis, particularly through genetic ablation of ACSL4 in CAR-T cells, substantially enhanced antitumor efficacy. Together, these findings identify iron-driven ferroptosis as a determinant of CAR-T cell dysfunction and a targetable barrier to durable CAR-T efficacy.