Reversing Ferroptosis Resistance in Breast Cancer via Tailored Lipid and Iron Presentation

Ferroptotic cancer therapy is promising in many scenarios where traditional cancer therapies show a poor response. However, certain types of cancers lack the long-chain acyl-CoA synthetase 4 (ACSL4), a key modulator of ferroptosis, resulting in therapy resistance and tumor relapse. Because ACSL4 is in charge of the synthesis of ferroptotic lipids (e.g., arachidonoylphosphatidylethanolamine/PE-AA), we postulated that direct delivery of PE-AA may reverse ferroptosis resistance induced by ACSL4 deficiency. To further increase the ferroptosis sensitivity, we employed the ferrocene-bearing polymer micelles to co-load PE-AA with an FDA-approved redox modulator, auranofin (Aur), targeting the thioredoxin reductase. The presence of ferrocene enabled triggered cargo release and iron production, which can sensitize ferroptosis by boosting autoxidation-mediated PE-AA peroxidation. The micellar system could impair redox homeostasis and induce lipid peroxidation in ACSL4-deficient MCF-7 cells. Moreover, the tailored micelles potently induced ferroptosis in MCF-7 tumors in vivo, suppressed tumor growth, and increased the mice's survival rate. The current work provides a facile means for reversing the ferroptosis resistance in ACSL4-deficient tumors.