Systematic Pan-Cancer Characterization of ST3GAL4 Reveals Its Prognostic and Immunologic Associations

Background: Sialylation, a key terminal glycosylation modification, plays a pivotal role in tumor progression and immune evasion. The sialyltransferase ST3GAL4 is implicated in individual cancers, but its pan-cancer landscape and systemic associations remain undefined. Methods: We performed an integrated multi-omics analysis using transcriptomic, proteomic, genomic, DNA methylation, and tumor microenvironment datasets from TCGA, CPTAC, GTEx, and other public resources. Immune associations were evaluated via TIMER2.0 and TISIDB. Experimental validation included immunofluorescence staining for ST3GAL4 protein in human tumor specimens. Results: ST3GAL4 exhibited pervasive, lineage-specific dysregulation across cancers. Elevated expression correlated with adverse prognosis, genomic instability, and specific RNA modification patterns. Tumor microenvironment analyses revealed significant associations: ST3GAL4 expression positively correlated with cancer-associated fibroblast and endothelial cell infiltration but was inversely associated with cytotoxic T-cell abundance. Functional enrichment implicated ST3GAL4 within glycosphingolipid metabolism and glycan biosynthetic pathways. In experimental models, its expression demonstrated context-dependent modulation following cytokine stimulation and immunotherapy. Immunofluorescence confirmed tumor-specific protein expression and its spatial co-occurrence with stromal and immune cell markers. Conclusion: This multi-omics study delineates a comprehensive pan-cancer atlas of ST3GAL4, establishing its association with aggressive tumor behavior, an immunosuppressive microenvironment, and core glycosylation pathways. These findings position ST3GAL4 as a potential cross-tumor node linking sialylation to immune evasion, providing a rationale for future mechanistic and therapeutic exploration.