The most prevalent metastatic skin cancer is keratinocyte-derived cutaneous squamous cell carcinoma (cSCC), the incidence of which is growing worldwide. Although the most common mutations in cSCC have been identified, its molecular pathogenesis is yet to be completely understood. At present, there are no biomarkers or therapeutic targets for high-risk cSCCs. Inflammation is part of the cSCC microenvironment. The complement system is the backbone of innate immune defense, and regulates immune and inflammatory responses.

In this study, the role of two complement components in cSCC progression was investigated. Additionally, the complement-targeted therapeutics under clinical and preclinical trials were comprehensively reviewed. Elevation of complement factor D (FD) expression was revealed in cSCC cells and cSCC tumors. The immunohistochemistry (IHC) analysis showed more intense FD labeling in invasive margins of human cSCC xenograft tumors, and in cytoplasm of tumor cells in recessive dystrophic epidermolysis bullosa-associated SCC, cSCC metastases, and metastatic and primary cSCCs vs. cSCC in situ, actinic keratosis and normal skin. Targeted inhibition of FD by small-molecule FD inhibitor danicopan (ACH-4471) suppressed ERK1/2 activation and proliferation of cultured cSCC cells. Furthermore, knockdown of complement factor I (FI) downregulated MMP-2 and -13 expressions by cSCC cells in vitro and in vivo, and inhibited invasion of cSCC cells in culture. FI overexpression upregulated the expression of MMP-2 and -13, increased ERK1/2 activation, and enhanced proliferation and invasion capacity of cSCC cells in vitro.

In conclusion, autocrine FD and FI promote the development and progression of cSCC, and can be identified as potential biomarkers and promising therapeutic targets in invasive cSCC. Besides, for the first time, the results propose smallmolecule FD inhibitor danicopan as a highly specific and sensitive drug for precision cSCC therapy.