Immunomodulation by glycosylation: bridging glycobiology to adaptive immunity and therapeutic innovation.

Adaptive immunity provides specific and long-lasting protection through antigen-specific responses and immune memory, a property that has been successfully harnessed in transformative immunotherapies. Advancing these treatments requires a deeper understanding of the molecular mechanisms that fine-tune immune activity. In this context, glycosylation, a ubiquitous and complex post-translational modification, is emerging as a central regulator. By shaping the structure and function of immune proteins, glycans critically regulate the behavior of T cells, B cells and antigen-presenting cells. This review summarizes current knowledge on how glycosylation governs key processes in acquired immunity, from antigen recognition and immune signal transduction to cell-cell interaction. We highlight that glycans can function directly as antigens or, more commonly, by forming distinct glyco-signatures on cell surfaces that sculpt immune response. Furthermore, we discuss the therapeutic implications of these insights and outline emerging strategies that target glycosylation pathways to enhance anti-tumor immunity, improve vaccine efficacy, and treat autoimmune disorders. A deeper integration of glycobiology into adaptive immunity is therefore pivotal for developing the next generation precision immunotherapies.