Terminal sialic acid residues on tumor cell surface glycans (Sia)

Terminal sialic acids are nine-carbon acidic sugars located at the outermost ends of glycan chains on cell surface glycoproteins and glycolipids (Source: Varki, A., Glycobiology, 2008). In many cancers, an overabundance of these residues, known as hypersialylation, serves as a potent mechanism for immune evasion by engaging inhibitory Siglec (Sialic acid-binding immunoglobulin-type lectin) receptors on various immune cells, such as NK cells and macrophages (Source: Rodriguez, E. et al., Nature Reviews Cancer, 2018). This interaction creates a "glyco-immune checkpoint" that dampens the anti-tumor immune response, similar to the PD-1/PD-L1 axis (Source: Läubli, H. & Varki, A., Trends in Immunology, 2020). Therapeutic strategies targeting these residues include the use of sialidase-antibody conjugates, such as E-602, to selectively remove sialic acids from the tumor surface or small molecule inhibitors of sialyltransferases to prevent their synthesis (Source: Palleon Pharmaceuticals; Gray, M.A. et al., Nature Chemical Biology, 2020). By stripping these terminal sugars, the tumor becomes more susceptible to immune-mediated destruction and exhibits reduced metastatic potential.

Other names

Sialic acidN-acetylneuraminic acidNeu5AcHypersialylated glycansTumor-associated carbohydrate antigensTACASialic acid-Siglec axis

Enzymatic desialylation of the tumor cell surface to remove immune-masking sialic acids and disrupt the inhibitory sialic acid-Siglec axis, thereby enhancing anti-tumor immunity (Source: Palleon Pharmaceuticals; Gray, M.A. et al., Nature Chemical Biology, 2020).