Sphingolipid metabolic subtyping defines SPHK1 as an oncogene and characterizes immunosuppressive TME features in gastric cancer

Abstract Gastric cancer (GC) exhibits profound heterogeneity and poor clinical outcomes, underscoring the need for improved prognostic stratification and deeper insights into metabolism-immune interactions within the tumor microenvironment (TME). Although sphingolipid metabolic reprogramming is known to influence TME remodeling, systematic GC subtyping based on sphingolipid metabolism-related genes (SMGs) and the spatial regulatory roles of key metabolic enzymes remain insufficiently characterized. Using TCGA RNA sequencing data, we performed unsupervised clustering of SMGs and identified two metabolic subtypes. Cluster A was marked by upregulated sphingolipid metabolism, extensive extracellular matrix remodeling, and enrichment of immunosuppressive pathways, corresponding to significantly worse survival. Cluster B showed enrichment of energy metabolic programs and increased inflammatory immune infiltration, aligning with a more favorable prognosis. Spatial transcriptomic analysis revealed SPHK1 enrichment at the tumor invasive front, where high SPHK1 expression correlated with increased dendritic cell and neutrophil infiltration but not CD8 + T cell accumulation, suggesting a myeloid-dominant immunosuppressive niche. Functionally, SPHK1 knockdown suppressed GC cell proliferation and migration, increased E-cadherin, decreased mesenchymal markers, and inhibited TGF-β1 signaling, confirming its role in EMT and tumor progression. Collectively, these findings identify sphingolipid metabolic remodeling and aberrant SPHK1 activation as key drivers of GC immune evasion and potential therapeutic vulnerabilities.