α-2,6-linked sialic acid-containing cell surface glycoprotein receptor (α2,6-Sia)

α-2,6-linked sialic acid-containing cell surface glycoprotein receptors are a class of proteins modified with terminal sialic acids in an α2,6-configuration, a process primarily mediated by the glycosyltransferase ST6Gal-I (Pinho & Reis, 2015, Nature Reviews Cancer). In the tumor microenvironment, hypersialylation of these receptors serves as a potent immune-evasive mechanism by engaging Sialic acid-binding immunoglobulin-type lectins (Siglecs) on the surface of myeloid cells, NK cells, and T cells, which transmits inhibitory signals (Boligan et al., 2020, Frontiers in Immunology). This "sialic acid-Siglec axis" functions similarly to traditional immune checkpoints like PD-1/PD-L1, effectively masking tumor cells from immune surveillance. Furthermore, α2,6-sialylation of specific receptors, such as integrins and EGFR, has been shown to enhance tumor cell motility, survival, and resistance to apoptosis (Döbelt & Rosiczky, 2020, Molecules). Therapeutic interventions, such as the sialidase fusion protein E-602, are designed to enzymatically remove these sialic acid residues, thereby "de-cloaking" the tumor and restoring an active immune response (Palleon Pharmaceuticals, 2023). Clinical development of these agents focuses on patients with high levels of α2,6-sialylation, often identified via lectin-based biomarkers like Sambucus nigra agglutinin (SNA).

Other names

α2,6-sialylated glycansNeu5Acα2-6Gal/GalNAcSialic acid α2,6-linkageHypersialylated tumor-associated carbohydrate antigensST6Gal-I products

Enzymatic desialylation of the tumor cell surface to abrogate the inhibitory sialic acid-Siglec immune checkpoint axis.