Cancer-associated alterations in O-GalNAc glycosylation.

Aberrant O-GalNAc glycans such as Tn, STn, and T are among the most consistent tumor-associated carbohydrate antigens, broadly expressed on carcinomas but largely absent from healthy epithelia. In parallel, O-glycans can also be modified to carry functional motifs, such as Lewis antigens. Rather than a simple shift from elongated to truncated structures, cancer-associated O-glycans form a heterogeneous repertoire of truncated and elongated glycoforms that coexist across the tumor glycocalyx. Collectively, both short and elongated cancer-associated O-glycans co-drive tumor formation through their simultaneous influence on multiple cancer hallmarks, including adhesion, receptor signaling, dissemination, and immune evasion. The latter occurs through interactions with glycan-binding proteins including Selectins, Siglecs, macrophage galactose-type lectin (MGL), and galectins. The stable expression of especially truncated O-glycans across cancer stages, as well as their driving influence on cancer progression, make short, truncated O-glycans attractive therapeutic targets. While early vaccine approaches had limited efficacy, strategies that couple O-glycan recognition with potent effector mechanisms have shown promise. This includes O-glycan-directed chimeric antigen receptor T cells (CARTs), T-cell bispecifics (TCBs), and particularly antibody-drug conjugates (ADCs), which have demonstrated strong preclinical activity. Looking forward, multi-specific antibodies, bio-orthogonal chemistry, and artificial intelligence-driven engineering are expected to enhance safety, selectivity, and improve patient stratification, helping to further exploit O-GalNAc glycans in precision oncology.