Adhesion to aggression: unravelling sLe^a and sLe^x in cancer metastasis

The sialylated Lewis antigens sLe^a and sLe^x are terminal glycans that are crucial for adhesive and signalling functions during cancer metastasis. As high affinity ligands for E-, P-, and L-selectins, these epitopes allow tumor cells to arrest, evade immune cells and extravasate in the vascular microenvironment, mimicking leukocyte trafficking. This review provides a detailed analysis of sLe^a/x biosynthesis, structure, function and their role in metastatic progression. We focus on the differential roles of glycoprotein versus glycolipid associated sLe^a/x, their glycosyltransferase mediated synthesis and the spatial trafficking mechanisms that govern their surface expression. We also highlight the carrier scaffolds and glyco-enzyme hierarchies that present the ligand across different cancers, mucins, integrins and glycosphingolipids. A section is dedicated to how exosome bound sLe^a/x primes pre-metastatic niche and immune modulation, a new perspective on glycan mediated systemic signaling. We also compile validated tumor specific profiles of sLe^a/x across several cancer types, linking structural expression to metastatic phenotypes. Additionally, we discuss emerging strategies targeting sLe^a/x pathways from glycosylation inhibitors to selectin blocking therapeutics and the translational challenges and opportunities. Overall, this synthesis shows the importance of sLe^a and sLe^x in metastasis and lays the foundation for their use as biomarkers and therapeutic targets in precision oncology.