Pharmacological targeting of ferroptosis in cancer: mechanisms, tumor immunity, and translational challenges

Abstract Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation and the failure of cellular antioxidant defenses. Its close integration with iron metabolism, lipid remodeling, and redox homeostasis has identified ferroptosis as a potentially exploitable vulnerability in cancer. This review critically examines the molecular and pharmacological determinants of ferroptotic sensitivity, including iron handling, acyl-CoA synthetase long-chain family member 4 (ACSL4)/lysophosphatidylcholine acyltransferase 3 (LPCAT3)-dependent lipid remodeling, and the glutathione peroxidase 4 (GPX4)–glutathione, ferroptosis suppressor protein 1 (FSP1)–coenzyme Q10, mitochondrial dihydroorotate dehydrogenase (DHODH), and GTP cyclohydrolase 1 (GCH1)–tetrahydrobiopterin defense systems. We discuss experimental ferroptosis inducers and clinically used drugs with reported ferroptosis-modulating activity, emphasizing differences in their mechanisms, strength of evidence, and translational relevance. Particular attention is given to the bidirectional interactions between ferroptosis and the tumor immune microenvironment. Although cytotoxic lymphocytes and interferon-gamma (IFN-γ) signaling may sensitize malignant cells to ferroptosis, excessive lipid peroxidation in cluster of differentiation 8-positive (CD8⁺) T cells, natural killer cells, dendritic cells, and other immune populations may impair antitumor immunity. These context- and cell-type-dependent effects support combination strategies involving immunotherapy, radiotherapy, and conventional or targeted anticancer treatments, but also define potential toxicities. We further discuss candidate biomarkers related to iron metabolism, lipid composition, antioxidant capacity, and immune context, as well as the need for patient stratification and targeted drug delivery. Successful clinical implementation will require selective induction of ferroptosis in malignant cells while preserving normal tissues and antitumor immune function. Ferroptosis should therefore be regarded as a conditional therapeutic vulnerability rather than a universally beneficial anticancer mechanism.