The Epigenetic Landscape and Exposome of Non-Melanoma Skin Cancer: Mechanisms, Biomarkers, and Therapeutic Perspectives

Accounting for over 1.2 million new diagnoses worldwide in 2022, non-melanoma skin cancer (NMSC) represents the most common human cancer, predominantly manifesting as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). NMSC serves as a powerful natural model for studying how environmental exposure, the exposome, reprograms the epigenome to drive carcinogenesis. Chronic ultraviolet radiation (UVR), the dominant risk factor, induces DNA damage and inflammation that dysregulate epigenetic enzymes (e.g., DNMTs, HDACs). These effects are layered with perturbations from β-HPV infection and cutaneous dysbiosis, altering DNA methylation, histone modifications, and non-coding RNA and miRNA expression in a multistep carcinogenic process. This review synthesizes the central role of epigenetic regulation as the critical interface between genetic susceptibility and cumulative exposome factors in NMSC pathogenesis. We integrate how UVR, HPV, and inflammation converge to remodel the keratinocyte epigenome. Finally, we evaluate the translational potential of this knowledge for refined risk stratification through epigenetic biomarkers and discuss emerging therapeutic strategies, including epidrugs, that target these dysregulated pathways for advanced NMSC management.