Lipid Metabolism and Ferroptosis Resistance in Dormant Breast Cancer Cells: Emerging Therapeutic Vulnerabilities

Late metastatic relapses still represent a major clinical challenge in breast cancer, particularly in hormone receptor-positive (HR+) disease, with dormant disseminated tumor cells (DTCs) playing a critical role in driving late metastatic relapses. In fact, these cells can persist in a quiescent, non-proliferative state in metabolically hostile microenvironments such as the bone marrow, where they can resist conventional therapies, driving metastatic relapses even years after primary tumor removal. Recent advances highlight the crucial role of lipid metabolism in protecting dormant DTCs from ferroptosis—a form of regulated cell death characterized by iron-dependent lipid peroxidation. Dormant DTCs can avoid lipid peroxidation by incorporating monounsaturated fatty acids (MUFAs) into membrane phospholipids through ACSL3 and SCD1 activity, while accumulating lipid droplets (LDs) that sequester oxidizable polyunsaturated fatty acids (PUFAs), thus limiting the substrates available for ferroptosis. In parallel, antioxidant systems such as the GPX4–glutathione axis further prevent lethal lipid-derived reactive oxidative species (ROS) accumulation. This review highlights the central role of lipid metabolism, redox regulation and ferroptosis resistance in dormant DTCs; it also explores emerging therapeutic opportunities to overcome dormancy-associated resistance and reduce late relapse risk in breast cancer.