Abstract
Glycan-mediated communication between immune cells and their environment is orchestrated by a structurally diverse set of lectin receptors whose exquisite ligand specificity governs both protective immunity and pathological immune evasion. Among these, the C-type lectin DC-SIGN, the proto- and chimera-type Galectins, and the immunoglobulin-like Siglecs occupy central positions in shaping innate and adaptive immune responses. Understanding the molecular basis of these interactions including the thermodynamics and kinetics of binding, the roles of multivalency and avidity, and the structural dynamics of recognition pockets is essential for both decoding immune regulation and developing precision therapeutics. This review presents a mechanistic and comparative analysis of glycan recognition across all three lectin families. We discuss how pathogens exploit these receptors to evade immunity, how tumors deploy hypersialylation and galectin secretion as non-canonical immune checkpoints, and how structural knowledge has enabled rational ligand-based drug design. Current therapeutic strategies including glycomimetic inhibitors, monoclonal antibodies, clustered regularly interspaced short palindromic repeats (CRISPR)-mediated glycoengineering, and chimeric antigen receptor T-cell (CAR-T) cell approaches are critically evaluated alongside emerging technologies in AI-assisted glycochemistry, single-cell glycomics, spatial glycoproteomics, and glycan nanoparticle delivery. We conclude by outlining a framework for precision glycoimmunotherapy in cancer, infection, fibrosis, and autoimmunity, positioning lectins as dynamic immune checkpoints whose structural plasticity makes them compelling and tractable drug targets.