SLFN5 as a dual-function oncogene and immune regulator: A pan-cancer multi-omics analysis linking prognosis, immune evasion, and therapeutic vulnerability

• SLFN5 correlates with advanced cancer stages, aggressive subtypes, and poor survival. • SLFN5 fosters an immunosuppressive tumor microenvironment, aiding immune evasion. • High SLFN5 predicts sensitivity to BET/HDAC and PARP inhibitors in certain tumors. • SLFN5 links to elevated TMB/MSI and DNA repair, affecting genomic instability. • SLFN5 serves as a stratification biomarker for immunotherapy and targeted therapies. This study delineates the dual oncogenic and immunomodulatory functions of SLFN5 across a spectrum of human malignancies. By integrating comprehensive multi-omics analyses in breast, liver, and ovarian cancers, we demonstrate that elevated SLFN5 expression is consistently associated with advanced tumor stage, remodeling of the tumor microenvironment toward a more aggressive phenotype, and poorer clinical outcomes. Mechanistically, SLFN5 displays a paradoxical immunoregulatory role: it facilitates the infiltration of immunosuppressive regulatory T cells (Tregs) and polarized macrophages, yet concurrently stimulates key immune checkpoint pathways. Functional enrichment analyses further underscore its central position in coordinating tumor-immune communication. Clinically, SLFN5 expression emerges as a predictive biomarker for heightened sensitivity to epigenetic therapies, including BET and HDAC inhibitors, and shows correlation with established markers of genomic instability, such as elevated tumor mutational burden (TMB) and microsatellite instability (MSI). Collectively, our results establish SLFN5 as a pleiotropic regulator residing at the crossroads of tumor progression and immune evasion. These findings not only provide a molecular rationale for targeting SLFN5 therapeutically but also offer a conceptual framework for designing combination immunotherapy strategies in SLFN5-high malignancies.