Cutaneous melanoma ranks as the fifth most common cancer in the United States and represents one of the deadliest forms of skin cancer. While recent advances in systemic targeted therapies and immunotherapies have positively impacted melanoma survival, the survival rate of stage IV melanoma remains at a meager 32%. Unfortunately, tumor resistance can impede the effectiveness of these treatments. Oxidative stress is a pivotal player in all stages of melanoma progression, with a somewhat paradoxical function that promotes tumor initiation but hinders vertical growth and metastasis in later disease. As melanoma progresses, it employs adaptive mechanisms to lessen oxidative stress in the tumor environment. Redox metabolic rewiring has been implicated in acquired resistance to BRAF/MEK inhibitors. A promising approach to enhance the response to therapy involves boosting intracellular ROS production using active biomolecules or targeting enzymes that regulate oxidative stress. The complex interplay between oxidative stress, redox homeostasis, and melanomagenesis can also be leveraged in a preventive context. The purpose of this review is to provide an overview of oxidative stress in melanoma, and how the antioxidant system may be manipulated in a therapeutic context for improved efficacy and survival.
Keywords: BRAF/MEK inhibitors; N-acetylcysteine (NAC); NRF2; ROS; antioxidants; glutathione; melanoma; oxidative stress; superoxide dismutase; thioredoxin reductase.