Simple SummaryTumor cells accumulate sialylation in tissues via the coordination of sialyltransferases and sialidases. Tumor sialylation can block receptor and ligand binding at a physical level and actively inhibit immune activation by binding to the Siglec receptor of immune cells, creating an immunosuppressive microenvironment. Blocking the sialylation–Siglec axis in tumor tissues could alleviate the suppression of the immune microenvironment.AbstractThe tumor microenvironment (TME), where the tumor cells incite the surrounding normal cells to create an immune suppressive environment, reduces the effectiveness of immune responses during cancer development. Sialylation, a type of glycosylation that occurs on cell surface proteins, lipids, and glycoRNAs, is known to accumulate in tumors and acts as a “cloak” to help tumor cells evade immunological surveillance. In the last few years, the role of sialylation in tumor proliferation and metastasis has become increasingly evident. With the advent of single-cell and spatial sequencing technologies, more research is being conducted to understand the effects of sialylation on immunity regulation. This review provides updated insights into recent research on the function of sialylation in tumor biology and summarizes the latest developments in sialylation-targeted tumor therapeutics, including antibody-mediated and metabolic-based sialylation inhibition, as well as interference with sialic acid–Siglec interaction.