Sialic acid-binding immunoglobulin-type lectin (Siglec)

Sialic acid-binding immunoglobulin-type lectins (Siglecs) are a family of transmembrane receptors primarily expressed on immune cells that function as glyco-immune checkpoints (Duan and Paulson, 2020). These receptors recognize sialic acid-containing glycans (sialoglycans) on cell surfaces, which typically serve as self-recognition signals to prevent inappropriate immune activation (UniProt). In many cancers, tumor cells undergo hypersialylation, creating a dense glycan shield that engages inhibitory Siglecs, such as Siglec-7, Siglec-9, and Siglec-15, on T cells, NK cells, and macrophages (Chen et al., 2019). This engagement triggers inhibitory signaling through immunoreceptor tyrosine-based inhibitory motifs (ITIMs), effectively dampening the anti-tumor immune response and allowing for immune evasion (Nature Reviews Cancer, 2023). Therapeutic strategies aim to disrupt this interface using monoclonal antibodies to block specific Siglec receptors or sialidase-based enzyme-antibody fusions, like E-602, to strip immunosuppressive glycans from the tumor surface (Palleon Pharmaceuticals, 2023). By preventing Siglec-mediated signaling, these therapies aim to restore the immune system's ability to recognize and eliminate malignant cells.

Other names

SIGLECSialic acid-binding lectinI-type lectinCD33-related SiglecsSialic acid-binding Ig-like lectin

Disruption of the inhibitory signaling pathway by blocking the interaction between sialic acid ligands on tumor cells and Siglec receptors on immune cells, or by enzymatic removal of sialic acids from the tumor surface to prevent receptor engagement.