Confronting Melanoma Radioresistance: Mechanisms and Therapeutic Strategies

cancers Confronting Melanoma Radioresistance: Mechanisms and Therapeutic Strategies

Simple Summary

Melanoma resistance to radiation therapy can be attributed to both intrinsic and acquired resistance mechanisms, such as enhanced DNA repair, hypoxia, and cancer stem cell activity, and is associated with treatment failure. Uncovering the molecular mechanisms of melanoma radioresistance may provide a foundation for more efficient and personalized melanoma therapies, reduce recurrence rates, and inspire further research into overcoming resistance in other radioresistant cancers, ultimately benefiting the broader oncology research community. This review primarily focuses on cutaneous melanoma, which represents the most common and extensively studied form of melanoma. Although the primary emphasis is on cutaneous melanoma, uveal melanoma is mentioned in rare instances as an example to illustrate specific concepts or phenomena, such as the unique characteristics of radiotherapy in this distinct melanoma subtype.

Abstract

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, 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, DNA repair mechanisms, hypoxia, altered metabolism, and melanin production. It also examines preclinical and clinical studies on novel therapeutic approaches, such as targeting cancer stem cell pathways, inhibiting DNA repair, modulating hypoxia-induced metabolic shifts, and combining radiotherapy with immunotherapies or targeted therapies. Promising strategies, such as radiotherapy-induced immune responses and advanced radiotherapy 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.