Abstract
Cutaneous melanoma is a highly aggressive skin cancer with rising incidence, driven by risk factors such as ultraviolet exposure, genetic predisposition, and immunosuppression. While surgical excision remains the primary treatment, interest in chemoprevention strategies is growing. Numerous natural and synthetic agents have shown preclinical promise, but evaluating their effectiveness is challenging due to their systemic effects on multiple cell types. This review provides a focused examination of the melanocyte-specific mechanisms of select agents that have been tested in clinical trials for melanoma chemoprevention. We discuss various molecular and cellular mechanisms driving the anti-melanoma properties of nonsteroidal anti-inflammatory drugs, statins, sulforaphane, vitamin D, and N-acetylcysteine. Despite promising preclinical and early clinical data, challenges remain regarding precise mechanisms, optimal dosing, long-term safety, and patient selection. Future research should focus on refining melanoma prevention strategies through well-designed clinical trials and personalized approaches integrating genetic and molecular risk factors.