SLAMF8 expression and prognostic significance in melanoma: A multi-omics and Mendelian randomization study

BackgroundMelanoma represents one of the most aggressive skin cancers, responsible for over 75% of skin cancer-related deaths despite comprising only 5% of cases. Despite therapeutic advances, patient responses remain variable and unpredicv. The Signaling Lymphocytic Activation Molecule (SLAM) family regulates immune cell communication, with SLAMF8 being predominantly expressed on myeloid cells. However, SLAMF8's specific role in melanoma pathogenesis remains largely unexplored.MethodsIn this retrospective integrative study, we systematically investigated SLAMF8's role in melanoma through multi-omics analyses using TIMER, GEPIA, and UALCAN databases, following the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for observational data reporting. Functional studies were conducted in A-375 and SK-MEL-28 melanoma cell lines using siRNA-mediated knockdown, followed by migration, invasion, and proliferation assays. DNA methylation patterns were analyzed via the SMART database, while mutation profiles were examined using cBioPortal and COSMIC. Immune infiltration analysis was performed through TIMER, and pathway associations were investigated using Gene Set Enrichment Analysis and protein-protein interaction networks. Finally, two-sample Mendelian Randomization analysis assessed the causal relationship between SLAMF8 expression and melanoma susceptibility.ResultsSLAMF8 expression was significantly higher in metastatic melanoma compared to primary tumors, with expression patterns varying across disease stages and between sexes. Higher SLAMF8 expression correlated with improved disease-free and overall survival. Functional studies demonstrated that SLAMF8 knockdown significantly enhanced melanoma cell proliferation, migration, and invasion. DNA methylation analysis revealed significant negative correlations between methylation at specific CpG sites and SLAMF8 expression, with hypermethylation associated with worse survival outcomes. Mutation analysis identified alterations in 10.21% of melanoma patients. Immune infiltration studies demonstrated strong correlations between SLAMF8 expression and enhanced immune cell presence. GSEA linked SLAMF8 to critical immune pathways including allograft rejection, inflammatory response, and interferon signaling. Mendelian Randomization analysis established a protective causal relationship between SLAMF8 and melanoma risk (OR = 0.39, 95% CI = 0.21-0.74, p = 3.34e-03).ConclusionOur study demonstrates that SLAMF8 plays a critical role in melanoma by suppressing tumor progression and modulating the immune microenvironment. Elevated SLAMF8 expression in metastatic melanoma is associated with improved patient survival, suggesting its utility as a prognostic biomarker. Furthermore, its tumor-suppressive effects and immune-regulatory functions highlight SLAMF8 as a promising therapeutic target for melanoma treatment strategies.