MC1R is a G protein-coupled receptor that serves as the primary regulator of human skin pigmentation and UV protection. Upon binding melanocyte-stimulating hormone (α-MSH), a product of the POMC precursor protein, MC1R couples to Gs proteins and activates adenylate cyclase, triggering cAMP-dependent signaling that promotes melanogenesis—the production of both eumelanin (brown/black) and pheomelanin (red/yellow) pigments 1. MC1R signaling also enhances DNA repair following UV irradiation 2, providing critical photoprotection. MC1R activity requires palmitoylation mediated by ZDHHC13, which can be enhanced by AMPK phosphorylation to strengthen signaling in individuals carrying loss-of-function red hair color (RHC) variants 3. Genetic variations in MC1R, particularly RHC variants associated with fair skin and poor tanning ability, significantly increase melanoma susceptibility 45. Notably, MC1R activation in melanoma cells suppresses T cell infiltration through GNAS-PKA-mediated inhibition of chemokines (CXCL9/10/11), promoting immune evasion and resistance to checkpoint blockade therapy 6. While CDKN2A mutations confer the strongest hereditary melanoma risk, MC1R represents a moderate genetic risk factor 7. These findings suggest MC1R as both a fundamental pigmentation regulator and a therapeutic target for melanoma prevention and immunotherapy.