Endothelial Sialyl Lewis X-Modified Integrin α3 Drives Fatty Acid Metabolic Reprogramming to Shape Th17 Plasticity in Bladder Cancer

Tumor endothelial cells (TECs) are active regulators of the tumor immune microenvironment, and their surfaces are enriched with diverse glycans, yet the mechanisms linking endothelial glycosylation to immune modulation remain unclear. Here, we show that sialyl Lewis X (sLeX) glycosylation of integrin α3 (ITGA3) in TECs promotes endothelial-to-mesenchymal transition (Endo-MT) by stabilizing Slug and repressing CDH5 transcription via the EGFR-AKT-GSK3β axis. This process is accompanied by downregulation of aldehyde dehydrogenase 3 family, member A2 (FALDH), with impaired fatty acid oxidation and decreased mitochondrial ROS. Reduced ROS levels suppress the secretion of pro-inflammatory cytokines IL1β and IL6 while enhancing TGFβ production, skewing CD4⁺ T cell differentiation toward Treg-like Th17 while reducing Th1-like Th17 cells. Functionally, sLeX-modified ITGA3 fosters an immunosuppressive and pro-tumorigenic microenvironment. These findings reveal a novel link between endothelial glycosylation, metabolic reprogramming, and immune regulation, highlighting sLeX-modified ITGA3 as a potential mediator of tumor immune evasion.