SLFN5 correlates with tumor immune microenvironment and clinical outcomes of immunotherapy in melanoma

Schlafen family member 5 (SLFN5) has been implicated in melanoma progression, but its expression landscape, immunomodulatory function, and prognostic value for patient survival remain poorly characterized. Here, we systematically analyzed multi-omics datasets, clinical cohorts, histopathological specimens and performed in vitro functional experiments to dissect the immunological functions of SLFN5 in melanoma. Transcriptomic profiling revealed significantly elevated SLFN5 expression in primary and metastatic melanoma relative to normal skin, with its expression gradually declining alongside deeper tumor invasion and advanced lymph node metastasis. High SLFN5 expression correlated with intratumoral infiltration of CD8⁺ cytotoxic T cells, abundant immune checkpoint molecules and elevated MHC antigen presentation gene levels. Gene set enrichment analysis confirmed prominent enrichment of type I and II interferon response signatures in SLFN5-high melanoma tumors. Consistently, higher SLFN5 expression correlated with extended overall and progression-free survival, and represented an independent protective prognostic indicator in multivariate Cox regression analysis. Histological evaluation of melanoma tissues further demonstrated abundant intratumoral lymphocytes in SLFN5-high specimens. Functional experiments confirmed that SLFN5-overexpressing melanoma cells enhanced CD8 T cell cytotoxicity, as evidenced by increased Granzyme+ and Perforin+ CD8 T cells in co-culture. Mechanistically, SLFN5 overexpression may trigger phosphorylation of STAT1 and STAT2 in melanoma cells, transcriptionally elevating the expression of antigen-presenting molecules HLA-A and HLA-DRB1. Moreover, high SLFN5 expression predicted better outcomes in immunotherapy-treated cohorts, including anti-PD-1, anti-CTLA-4, and anti-PD-L1 regimens. Our findings identify SLFN5 as a prognostic and immunologically biomarker in melanoma. SLFN5 may serve as a prognostic biomarker for immunotherapy responsiveness, laying a foundation for its potential clinical utilization to guide immunotherapy.