The Glycocalyx: Barriers and Opportunities at Cell–Cell Encounters

ABSTRACT The glycocalyx, a carbohydrate‐rich, gel‐like layer that coats every mammalian cell, is the first point of contact between cells in tissues. It therefore critically influences these encounters, impacting their mechanical, electrical, and chemical features that ultimately determines the outcome of cell–cell contacts. The immune system and immune cell interactions are especially dependent on the surveillance and sensing of glycocalyces at transient cell–cell contacts. Here, the integration of information perceived in the glycocalyx determines immune cell decisions ranging from phagocytosis to target killing. To avoid detection and removal, malignant cell types and pathogens often construct an elaborate glycocalyx that shrouds neoantigens and other ligands to curtail these immune responses. Therapeutics have recently been devised to diminish or overcome the glycocalyx barrier in an effort to stimulate an immune response, especially in the context of mounting antitumor immunity. We discuss the general features of the glycocalyx—including those that afford immune evasion of cancers and pathogens—and provide an update on clinical strategies that are being developed to target this barrier.