Actinic Keratosis at the Crossroads of Inflammation and Cutaneous Dysbiosis

Actinic keratosis (AK) represents an early stage of keratinocyte carcinogenesis and has long been attributed primarily to cumulative ultraviolet (UV) radiation-induced genetic damage. However, increasing evidence suggests that AK arises within a complex cutaneous microenvironment, in which chronic inflammation, oxidative stress, immune dysregulation, and alterations of the skin microbiota interact to promote and sustain field cancerization. UV exposure not only drives mutational events in epidermal keratinocytes, but also disrupts barrier integrity and local immune surveillance, reshaping microbial community structure on photodamaged skin. Recent studies reveal a characteristic profile in AK, characterized by reduced microbial diversity, depletion of protective commensals, and enrichment of opportunistic taxa, most notably Staphylococcus aureus. Experimental and clinical data suggest that S. aureus may act as a microbial cofactor in AK by amplifying proinflammatory and pro-oxidant signaling, inducing genotoxic stress, impairing DNA repair pathways, and modulating local immune responses in a manner consistent with early carcinogenic progression. Concurrent loss of commensal bacteria and fungi with immunomodulatory functions may further destabilize epidermal homeostasis, potentially reinforcing a self-perpetuating inflammatory loop. This perspective review synthesizes current molecular, immunologic, and microbial evidence to elucidate the role of host-microbe interactions in AK arising on chronically UV-exposed skin. Finally, we discuss how targeting inflammation-microbiota crosstalk may open new opportunities for risk stratification, prevention, and therapeutic intervention across the AK-cutaneous squamous cell carcinoma spectrum.