Short Mucin-Type <i>O</i> -Glycans in Cancer: Biomarker and Therapeutic Potential amid Analytical Barriers

Mucin-type O-glycans are abundant protein modifications that regulate cell signalling, adhesion, and immune interactions. In cancer, their biosynthetic pathways are frequently disrupted, leading to the accumulation of truncated structures, such as Tn antigen and sialyl-Tn (STn). These aberrant glycans remodel the glycocalyx, alter receptor clustering, and drive key hallmarks of malignancy, including immune evasion, invasion, and therapy resistance. Over the past decade, increasing evidence has linked short O-glycans to poor prognosis across multiple tumour types, highlighting their potential as diagnostic and prognostic biomarkers. Moreover, their restricted expression in normal tissues positions them as attractive targets for therapeutic intervention, including monoclonal antibodies, antibody-drug conjugates, and CAR-T cell strategies. However, clinical translation remains limited by major analytical challenges. The structural diversity of O-glycans, their low abundance, and the lack of broadly specific enzymes for glycan release hinder comprehensive characterization. Recent advances in glycoproteomics, glycomics, and antibody engineering are beginning to overcome these barriers, enabling site-specific mapping and improved detection of cancer-associated glycoforms. This review summarizes current knowledge on the biosynthetic origins, biological roles, and clinical relevance of truncated O-glycans in cancer, while critically discussing emerging technologies and future directions for their integration into precision oncology.