Sialic acids are the terminal monosaccharides of the glycocalyx that play a crucial role in shaping cell-cell interactions. They are strongly involved in regulating immune recognition and tissue homeostasis. In cancer, abnormal sialylation rewires the tumor microenvironment by increasing ligands for inhibitory Siglecs, suppressing immune effector functions, and aiding metastatic spread. This review offers a comprehensive overview of the dual role of sialyltransferases (the “writers”) and Siglecs/Selectins (the “readers”) in cancer progression. The authors explore the structural and functional diversity of these molecules, their dysregulation in malignancy, and their effects on tumor–immune interactions. Finally, emerging therapeutic strategies are discussed, including sialyltransferase inhibitors, sialidase conjugates, and Siglec-targeted immunotherapies, which together highlight the sialome as a promising target in cancer treatment.
