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Short mucin-type O-glycans in cancer: biomarker and therapeutic potential amid analytical barriers
Henrique Sousa1,2, Inês A B Ribeiro1,2, Marta Falcão1,2,3
1UCIBIO - Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University of Lisbon, Caparica, 2829-516, Portugal.
Abstract:
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.
Insights
Truncated mucin-type O-glycans like Tn antigen and sialyl-Tn (STn) are linked to cancer progression and poor prognosis. Advances in analytical techniques offer new opportunities for their use as cancer biomarkers and therapeutic targets.
Area of Science:
- Biochemistry
- Glycobiology
- Cancer Biology
Background:
- Mucin-type O-glycans are crucial protein modifications involved in cell signaling and immune responses.
- Disrupted O-glycan biosynthesis in cancer leads to aberrant structures like Tn antigen and sialyl-Tn (STn), promoting malignancy.
- These truncated glycans are associated with poor prognosis and are potential biomarkers and therapeutic targets.
Purpose of the Study:
- To review the biosynthetic origins, biological roles, and clinical significance of truncated O-glycans in cancer.
- To discuss the analytical challenges hindering clinical translation of these glycoforms.
- To highlight emerging technologies and future directions for integrating truncated O-glycans into precision oncology.
Main Methods:
- Review of current literature on O-glycan biosynthesis, cancer biology, and analytical techniques.
- Discussion of glycoproteomics, glycomics, and antibody engineering advancements.
- Critical analysis of challenges and opportunities for clinical application.
Main Results:
- Truncated O-glycans (Tn antigen, STn) are prevalent in cancer, driving hallmarks of malignancy.
- These aberrant glycans serve as potential diagnostic and prognostic biomarkers.
- Emerging technologies are improving the characterization and detection of cancer-associated glycoforms.
Conclusions:
- Truncated O-glycans play significant roles in cancer development and progression.
- Overcoming analytical challenges is key to leveraging these glycans as biomarkers and therapeutic targets.
- Future directions involve integrating advanced glycomics and antibody engineering for precision oncology.
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