Dysregulated Sialylation in Cancer: From Immunosuppressive Microenvironment to Siglec-Targeted Therapeutics

Sialic acid, typically positioned at the terminal ends of glycoprotein or glycolipid chains via glycosyltransferase activity, is indispensable for intercellular recognition and signal transduction. Aberrant sialylation has been implicated in disrupted cell communication and oncogenic signaling, contributing to carcinogenesis. Consequently, targeting sialic acid metabolism has emerged as a promising strategy for cancer diagnosis and therapy. This review first delineates the physiological biosynthesis of sialic acid and molecular mechanisms underlying its pathological dysregulation. We then examine the sialic acid–Siglec axis as an immune checkpoint in cancer immunotherapy, highlighting its functional convergence and divergence from the PD-1/PD-L1 pathway. Furthermore, we elucidate how aberrant sialylation drives malignant transformation. Finally, we synthesize current therapeutic strategies targeting the sialic acid–Siglec axis, with particular emphasis on implementing nanomaterial-based platforms in clinical translation. These advances may yield novel diagnostic tools and therapeutic targets for glycobiology-guided precision medicine.