MC1R, eumelanin and pheomelanin: their role in determining the susceptibility to skin cancer Original paper

What was reviewed?

mc1r-eumelanin-pheomelanin-skin-cancer is the central theme of this invited review, which synthesizes mechanistic and translational evidence linking melanocortin 1 receptor (MC1R) signaling to the balance of eumelanin versus pheomelanin production and, in turn, susceptibility to melanoma and other skin cancers. The authors describe how keratinocyte–melanocyte cross-talk after ultraviolet radiation (UVR) injury increases α-melanocyte–stimulating hormone (α-MSH) and other mediators that activate MC1R on melanocytes, raising cAMP and inducing MITF-driven expression of tyrosinase (TYR), TRP1, and DCT/TRP2 enzymes that bias melanogenesis toward photoprotective eumelanin rather than pheomelanin. They also emphasize that pigmentation biology is not merely “UV blocking”: melanin chemistry influences oxidative stress, immune tone, and carcinogenic pathways independent of UV exposure, especially in red hair/fair skin MC1R loss-of-function backgrounds.

Who was reviewed?

The review integrates data from multiple experimental systems and clinical/epidemiologic observations rather than enrolling a single patient cohort. Human relevance is framed around pigmentation phenotypes (e.g., red hair, freckles, poor tanning) associated with inactivating MC1R variants such as R151C, R160W, and D294H, which are linked to increased melanoma and possibly nonmelanoma skin cancer risk. Animal evidence heavily features murine coat-color genetics (e.g., C57BL/6 vs agouti strains like C3H) used as biologic analogs of human eumelanin- versus pheomelanin-biased pigmentation, including models showing that pheomelanin-rich backgrounds amplify melanoma susceptibility even without UVR exposure when combined with oncogenic drivers (notably BRAF-activated contexts discussed by the authors). Immune cell biology is covered broadly because MC1R is expressed not only on melanocytes but also on keratinocytes, endothelial cells, and many innate/adaptive immune cells, allowing MC1R signaling to shape inflammation and tumor surveillance across tissues.

Most important findings

The most clinically consequential synthesis is that eumelanin is largely protective through UV scattering/absorption and antioxidant activity, whereas pheomelanin is photounstable and can be intrinsically procarcinogenic by driving reactive oxygen species (ROS) generation and depleting intracellular antioxidants (notably glutathione/cysteine pools) during its synthesis. This creates a redox environment that can promote DNA damage with or without UVR and may also impair antitumor immunity by limiting cysteine availability for T-cell activation and by ROS-mediated suppression of CD8+ T-cell function. The authors highlight a pivotal genetic concept for risk stratification: MC1R loss-of-function shifts melanogenesis away from eumelanin toward pheomelanin and simultaneously alters inflammatory/immune signaling, potentially influencing both tumor initiation and immune editing. Importantly for microbiome-signature use, this paper does not report microbiome taxa, metagenomic pathways, or microbial metabolite associations; therefore, there are no microbial signatures to index from this review.

Key implications

Clinically, the review supports using MC1R genotype and pigmentation phenotype as biologically grounded markers of melanoma susceptibility, including risk that may not be fully explained by UV exposure history alone. It also reframes “red-hair risk” as partly driven by pheomelanin-associated oxidative stress and immune suppression, suggesting that prevention and surveillance strategies in MC1R-variant individuals should consider both photoprotection and broader oxidative/inflammatory context. For translational therapeutics, MC1R agonism (or downstream cAMP pathway augmentation) is positioned as a plausible strategy to bias toward eumelanin and potentially temper harmful inflammation, though the authors also acknowledge the complexity that immunomodulation could, in some contexts, support tolerogenic pathways. From a microbiome-database perspective, this article is best indexed as a host-genetics/host-pigment/immune–oncology mechanistic review with no direct microbiome signature outputs.

Citation

Nasti TH, Timares L. MC1R, eumelanin and pheomelanin: their role in determining the susceptibility to skin cancer. Photochem Photobiol. 2015;91(1):188-200. doi:10.1111/php.12335