Tissue-specific factors that govern the sialoglycan-Siglec axis in cancer

Aberrant sialylation is a persistent glycosylation change in cancer that reshapes interactions within the tumour microenvironment through the display of sialylated glycans (sialoglycans) on malignant and stromal cells. Many sialoglycans engage sialic acid-binding immunoglobulin-like lectins (Siglecs), a family of receptors expressed predominantly by immune cells that frequently transmit inhibitory signals and function as glyco-immune checkpoints. Increasing evidence indicates that tumour hypersialylation suppresses myeloid and lymphoid anti-tumour activity, promotes immune evasion, and contributes to metastatic behaviour. However, both sialoglycan repertoires and Siglec expression patterns vary markedly across cancer types and disease states, suggesting strong dependence on tissue context and tumour composition. In the present review, we discuss how tissue-of-origin programmes and lineage state establish basal sialyltransferase expression and constrain the sialoglycan landscape available to tumours. We highlight emerging single-cell evidence that stromal populations, particularly cancer-associated fibroblasts, can acquire hypersialylation and actively generate immunosuppressive Siglec ligands. We also examine how transcriptional and oncogenic regulators, including SOX2, MYC, and androgen receptor signalling, reprogramme sialyltransferase expression to produce tumour-specific sialoglycan profiles. Finally, we consider how standard-of-care therapies alter both ligand availability and immune composition, thereby dynamically modifying the sialoglycan-Siglec axis during treatment and resistance. Understanding these context-dependent determinants will be critical for interpreting sialylation in cancer biology and for designing effective therapeutic strategies targeting sialoglycan-Siglec interactions.