Sialic acid residues on tumor-associated stromal cells

Sialic acid residues on tumor-associated stromal cells, such as cancer-associated fibroblasts (CAFs) and mesenchymal stem cells (MSCs), are hypersialylated glycans primarily in α2,6-linkages, driven by sialyltransferases like ST6GALNAC6. These residues act as ligands for inhibitory Siglec receptors (e.g., Siglec-10 on macrophages and NK cells, Siglec-G in mice), inducing immune suppression by impairing phagocytosis, cytotoxicity, and promoting M2-like macrophage polarization and PD-L1/IL-10 expression. In colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC), stromal sialylation exceeds that on epithelial tumor cells, correlates with poor prognosis in stromal-rich tumors, and drives inflammation-associated metastasis. Targeting via sialidase treatment or sialyltransferase knockdown reduces tumor growth, enhances NK and macrophage activation, and restores anti-tumor immunity in preclinical models.[1][2][7]

Other names

Stromal sialic acidsHypersialylated glycans on stromal cellsSiglec ligands on stromal cells

Desialylation restores macrophage phagocytosis and NK cell cytotoxicity. Inhibition of sialyltransferases (e.g., ST6GALNAC6) reduces Siglec ligand expression. Disruption of sialic acid/Siglec axis enhances anti-tumor immunity.