Ferroptosis: A Targetable Vulnerability for Melanoma Treatment.

Melanoma is a devastating form of skin cancer characterized by a high mutational burden, limited treatment success, and dismal prognosis. Although immunotherapy and targeted therapies have significantly revolutionized melanoma treatment, the majority of patients fail to achieve durable responses, highlighting the urgent need for novel therapeutic strategies. Ferroptosis, an iron-dependent form of regulated cell death driven by the overwhelming accumulation of lipid peroxides, has emerged as a promising therapeutic approach in preclinical melanoma models. A deeper understanding of the ferroptosis landscape in melanoma based on its biology characteristics, including phenotypic plasticity, metabolic state, genomic alterations, and epigenetic changes, as well as the complex role and mechanisms of ferroptosis in immune cells could provide a foundation for developing effective treatments. In this review, we outline the molecular mechanisms of ferroptosis, decipher the role of melanoma biology in ferroptosis regulation, reveal the therapeutic potential of ferroptosis in melanoma, and discuss the pressing questions that should guide future investigations into ferroptosis in melanoma.