Mucin-type O-glycans

Mucin-type O-glycans are complex carbohydrate structures covalently attached to the serine or threonine residues of mucin proteins, forming a dense glycocalyx on mucosal surfaces such as the gastrointestinal, respiratory, and urogenital tracts [1, 7, 15]. These glycans are essential for the viscoelastic properties of mucus, providing a physical barrier against pathogens and mechanical stress while also serving as a nutrient source and docking site for commensal microbiota [3, 19, 23]. In pathological conditions, particularly cancer, the glycosylation machinery is often disrupted, resulting in the expression of truncated or hypersialylated glycans known as tumor-associated carbohydrate antigens (TACAs) [2, 12, 14]. These aberrant structures, such as the Tn and Sialyl-Tn antigens, facilitate tumor cell invasion, metastasis, and immune evasion by interacting with host receptors like selectins and siglecs [5, 15, 16]. Consequently, these glycan moieties have emerged as high-priority therapeutic targets for the development of monoclonal antibodies, antibody-drug conjugates (ADCs), and CAR-T cell therapies designed to selectively eliminate malignant cells while sparing healthy tissue [8, 11, 14, 17]. Beyond oncology, mucosal glycans are being explored as targets for treating inflammatory bowel disease and preventing infectious diseases by modulating microbial adhesion [20, 21, 22].

Other names

Mucosal glycan moieties on mucinsMucin-associated glycansO-glycans on mucinsTumor-associated carbohydrate antigensTACAsMucosal oligosaccharidesMucin glycans

Therapeutic strategies targeting these moieties involve the use of monoclonal antibodies, antibody-drug conjugates (ADCs), and CAR-T cells to recognize aberrant tumor-associated carbohydrate antigens (TACAs), leading to immune-mediated cell death via antibody-dependent cellular cytotoxicity (ADCC) or direct T-cell lysis [8, 13, 14, 15]. Additionally, small molecule inhibitors of glycosyltransferases (e.g., GCNT3 inhibitors) can disrupt the synthesis of these glycans to reduce mucus-mediated chemoresistance or tumor growth [5, 12]. In the context of infection, glycomimetics can act as decoys to competitively inhibit the binding of pathogens to mucosal surfaces [1, 20, 22].