CD33 drives cutaneous melanoma: mendelian randomization confirms causality, multi-omics and in vitro experiments reveal M2 macrophage polarization-mediated progression

Background Cutaneous melanoma (CM), one of the most prevalent types of melanomas globally, continues to increase in incidence and mortality. Despite significant advances in targeted and immune therapies, most patients fail to achieve durable response; high rates of immune resistant and recurrence underscore the urgent need for novel therapeutic targets to improve prognosis and treatment outcomes. Materials and Methods Mendelian randomization (MR), summary-data-based MR (SMR) and colocalization analyses were employed to explore potential drug targets of CM via summary data from FinnGen cohorts (melanoma of skin: nCase = 3194, nControl = 314 193; melanoma in situ: nCase = 980, nControl = 313 899; melanoma of uvea: nCase = 293, nControl = 345 118), 731 immune cell traits (N = 3757) from the GWAS Catalog and protein quantitative trait loci (pQTL) in plasma from the deCODE genetics database. Bulk transcriptomes from the TCGA, GTEx and GENT2 databases, as well as single-cell transcriptomes from the GEO DataSets and published datasets, were analyzed to uncover potential mechanisms of CM development, which were then validated by in vitro experiments. Results Eight immune cell traits were positively related with both melanoma of skin and melanoma in situ, among these, six traits were CD33 mean fluorescence intensity (MFI) on immune cells. MR analysis of CD33 cis-pQTL also showed positive correlation and cis-pQTL data of CD33 pass SMR and HEIDI test both in melanoma of skin and melanoma in situ. The causal relationship between CD33, immune cell traits and cutaneous melanoma was further verified by colocalization analysis with a medium degree of confidence. Analysis of bulk transcriptome and single-cell transcriptome data revealed that CD33, which is mainly expresses on Macrophage/Dendritic cells in the tumor microenvironment (TME) of cutaneous melanoma, related with M2 macrophages differentiation. The results of in vitro experiments demonstrated that CD33 downregulation could inhibit M2 macrophages polarization, and decreased CD33 expression on M2 macrophages could inhibit proliferation and migration of melanoma cells. Conclusion By integrating MR, multi-omics transcriptome analysis and in vitro experiments validation, the present study revealed that CD33 could facilitate CM development by promoting M2 macrophages polarization.