Confronting Melanoma Radioresistance: Mechanisms and Therapeutic Strategies

Melanoma is a highly aggressive skin cancer with survival rates varying significantly based on stage and genomic characteristics. While localized melanoma has favorable outcomes, metastatic melanoma is associated with poor prognosis and limited treatment options. Radiotherapy (RT), one of the most commonly used cancer treatments, is less effective in melanoma due to its intrinsic radioresistance. This review discusses the current knowledge about the biological mechanisms contributing to melanoma radioresistance, including the role of cancer stem cells (CSCs), DNA repair mechanisms, hypoxia, altered metabolism, and melanin production. It also examines preclinical and clinical studies on novel therapeutic approaches, such as targeting CSC pathways, inhibiting DNA repair, modulating hypoxia-induced metabolic shifts, and combining RT with immunotherapies or targeted therapies. Promising strategies, such as RT-induced immune responses and advanced RT techniques, show the potential to overcome resistance. However, melanoma’s heterogeneity and the limited clinical validation of these approaches remain significant challenges. Integrated therapeutic strategies targeting the multifaceted mechanisms of melanoma radioresistance are essential to improve treatment outcomes. Further clinical validation and personalized approaches are needed to address the heterogeneity of melanoma and enhance the efficacy of novel interventions.