Beyond a passive coating: The cancer glycocalyx as a dynamic biophysical and immune interface

The glycocalyx is a carbohydrate-rich layer formed by glycoproteins, glycolipids, proteoglycans, and glycosaminoglycans at the outer cell surface. In cancer, this layer is not a passive coating. Its thickness, composition, charge, and nanoscale organization are altered by oncogenic signaling, dysregulated glycosyltransferases, protease-mediated shedding, and reciprocal interactions with stromal and immune cells. These changes affect how tumor cells sense force, bind the extracellular matrix, cluster receptors, evade immune surveillance, survive in circulation, and arrest at distant vascular beds. Studies in the past decade have linked a bulky glycocalyx to integrin activation and growth factor signaling, identified hyaluronan-CD44 and selectin-dependent steps in metastatic dissemination, and placed the sialoglycan-Siglec axis among the immune suppressive circuits operating in the tumor microenvironment. Meanwhile, pathology, imaging, glycoproteomics, and liquid-biopsy studies have started to define glycocalyx-derived biomarkers with diagnostic and prognostic value, especially in hepatocellular carcinoma, pancreatic cancer, breast cancer, and hematologic malignancies. This review summarizes the structure of the cancer glycocalyx, the molecular programs that remodel it, and the consequences of these changes for tumor progression. It also discusses analytical approaches, biomarker development, and therapeutic strategies aimed at mucins, proteoglycans, glycosyltransferases, hyaluronan signaling, heparanase, and tumor-associated sialoglycans. A central theme is that the glycocalyx should be viewed as an integrated biophysical and signaling interface, and its clinical value will depend on spatially resolved, context-specific analysis rather than single-marker measurements alone.