Immunosenescence and Inflammaging in the Pathogenesis of Non-Melanoma Skin Cancer

Non-melanoma skin cancer (NMSC) is the most frequently diagnosed malignancy worldwide, and its incidence rises disproportionately with age. While cumulative ultraviolet (UV) exposure is the dominant recognised risk factor, it does not fully account for the steep age-associated increase in NMSC, suggesting that additional, underrecognised mechanisms operate in older skin. This review synthesises evidence that immune senescence (the age-related remodelling of innate and adaptive immunity) is a central and partly modifiable driver of NMSC aetiopathogenesis. We first outline the classical risk factors and the epidemiological and economic burden of NMSC, and revisit the proposal to regard recurrent NMSC as a chronic disease. We then examine four interlocking, age-associated processes: the accumulation of senescent cells and their pro-inflammatory secretory phenotype (“inflammaging”) in the skin microenvironment; UV-induced suppression of cutaneous immune function; age-related dysbiosis of the skin microbiome and its impact on antitumour immunity; and the systemic decline of T-cell-mediated tumour immunosurveillance. We integrate these processes into a framework in which immune senescence contributes to the progression of accumulated cutaneous damage to overt malignancy, and consider the implications for prevention (including senotherapeutics, microbiome modulation, and immune-stratified surveillance) that extend beyond UV-directed measures alone.