Sialylation-Siglec glyco-immune checkpoints in hepatocellular carcinoma: mechanisms of immune evasion, therapeutic resistance, and postoperative recurrence

Postoperative recurrence and incomplete responses to immunotherapy remain major obstacles to the long-term control of hepatocellular carcinoma (HCC). Tumor-associated sialylation may promote immune escape by generating glycans that bind inhibitory members of the sialic acid-binding immunoglobulin-like lectin (Siglec) family on immune cells. This review critically examines HCC-specific evidence on abnormal sialylation, Siglec-related dysfunction of natural killer cells and macrophages, treatment-associated glycan remodeling, and possible links to molecular residual disease and postoperative recurrence. Glycan patterns vary substantially between tumors and within individual tumors. Total sialic acid abundance and the expression of a single sialyltransferase therefore provide only part of the information needed to identify functional Siglec ligands. Their activity also depends on glycan structure, chemical modifications, the molecule carrying the glycan, ligand density, surface accessibility, and spatial organization. The strongest HCC-specific evidence concerns the interaction between Siglec-9 and natural killer cells. Supporting findings include receptor and ligand expression, close spatial proximity within tumors, associations with adverse clinical outcomes, and recovery of natural killer-cell activity after pathway inhibition in preclinical models. Siglec-10-high tumor-associated macrophages are associated with an immunosuppressive myeloid state. Their endogenous ligands and receptor-specific roles in vivo require further characterization. In sorafenib-resistant HCC models, increased ST3 β-galactoside α-2,3-sialyltransferase 1 (ST3GAL1) expression accompanies greater Siglec-7 and Siglec-9 probe binding, while ST3GAL1 silencing improves natural killer-cell-mediated cytotoxicity. These findings support a functional contribution of altered glycosylation to treatment-related immune escape. Glycocalyx-dependent changes in adhesion, migration, and survival may also contribute to dissemination and residual-cell persistence alongside immune evasion. Direct studies are now needed to determine whether sialylation-Siglec signaling helps residual HCC cells survive after curative-intent therapy. Clinical translation will require identification of specific glycan-carrier pairs, spatial mapping of receptor-ligand contacts, receptor-specific validation in species-appropriate models, and prospective evaluation of glyco-immune biomarkers alongside circulating tumor DNA and established clinicopathological factors across HCC etiologies. Overall, current evidence identifies the sialylation-Siglec system as a biologically plausible and cell-specific immune-evasion network. It also provides a framework for biomarker-guided evaluation of Siglec-directed therapies and tumor-targeted desialylation and future studies of its contribution to HCC recurrence.