Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder, resulting from genetic defects in the nucleotide excision repair (NER) pathway. It predisposes individuals to skin cancers, including melanoma. The melanoma microenvironment is enriched with inflammatory mediators, particularly macrophages, which may serve as prognostic biomarkers or therapeutic targets. While inflammation is linked to melanoma outcomes, its role in carcinogenesis among XP patients remains poorly understood.

We assessed the cytokine profiles in the sera of XP-melanoma patients, as well as the expression level of a pan-macrophage marker (CD68), M2-markers CD163, and M1-associated nitric oxide synthase (iNOS) expression.

XP patients exhibited significantly reduced levels of iNOS, MIP-1β, MCP-1, and IL-33, indicating an impaired inflammatory and macrophage-mediated immune response. We also found that IL-33 and iNOS levels were positively correlated with the density of inflammatory infiltrates. Moreover, in vitro assays using G361 melanoma cells demonstrated that both pro-inflammatory macrophage-conditioned media and exogenous IL-33 suppressed tumor cell proliferation.

This study emphasizes the need for specific macrophage biomarkers and proposes local interleukin-33 delivery as a potential therapy for poorly infiltrated melanoma. This also suggests that NER-deficient patients may exhibit unique molecular profiles, warranting personalized treatment.