The Role of Macrophage Migration Inhibitory Factor and Its Homolog D-Dopachrome Tautomerase in Ultraviolet Radiation-Induced Carcinogenesis: New Insights Into Skin Cancer Mechanisms.

BACKGROUND/PURPOSE: Ultraviolet (UV) radiation is a key environmental carcinogen implicated in the development of various skin malignancies. Recent studies highlight the pivotal roles of macrophage migration inhibitory factor (MIF) and its homolog D-dopachrome tautomerase (DDT) in UV-induced skin carcinogenesis. This review aims to consolidate current knowledge of how MIF and DDT contribute to tumor initiation and progression under UV stress, with a focus on their biological functions, signaling pathways, and therapeutic potential.

METHODS

This narrative review synthesizes findings from basic, translational, and clinical studies examining MIF and DDT in the context of UV-mediated skin carcinogenesis. The literature was selectively reviewed to highlight mechanistic insights, pathological significance, and emerging therapeutic strategies.

RESULTS

Both MIF and DDT are upregulated upon UVB exposure and promote tumorigenesis by suppressing p53-mediated apoptosis, enhancing inflammatory signaling, and modulating the tumor immune microenvironment. Transgenic mouse models demonstrate that overexpression of either cytokine accelerates UVB-induced tumor formation, while inhibition reduces tumor burden. Although MIF and DDT share CD74-mediated pathways, they exhibit mechanistically distinct yet functionally complementary roles. In addition to melanoma, emerging evidence suggests involvement in non-melanoma skin cancers, particularly cutaneous squamous cell carcinoma (cSCC). Selective small-molecule inhibitors are under development, and expression profiles of MIF and DDT are being evaluated as biomarkers for prognosis and response to immunotherapy.

CONCLUSION

MIF and DDT are critical mediators of UV-induced skin carcinogenesis. Their overlapping yet non-redundant signaling properties and emerging clinical relevance suggest that targeting these cytokines may offer new opportunities for prevention, diagnosis, and treatment of UV-induced skin cancers.