Mathieu Decloquement, Matthew S. Macauley
Sialic acids are the terminal monosaccharides of the glycocalyx that critically shape cell-cell interactions and are strongly implicated in regulating immune recognition and tissue homeostasis. In cancer, aberrant sialylation rewires the tumor microenvironment by enhancing ligands of the inhibitory Siglecs, suppressing immune effector functions, and facilitating metastatic dissemination. This review provides a comprehensive synthesis of the dual role of sialyltransferases (the "writers") and Siglecs/Selectins (the "readers") in cancer progression. We examine the structural and functional diversity of these molecules, their dysregulation in malignancy, and their impact on tumor-immune dynamics. Finally, we highlight emerging therapeutic strategies, including sialyltransferase inhibitors, sialidase conjugates, and Siglec-targeted immunotherapies, which collectively position the sialome as a tractable frontier in cancer treatment.