Sialic acid-binding immunoglobulin-type lectin (Siglec) (Siglec)

Sialic acid-binding immunoglobulin-type lectins (Siglecs) are a family of cell-surface transmembrane receptors that recognize sialic acid-containing glycans, primarily functioning as regulators of the immune system (Crocker, P. R., et al., 2007, Nature Reviews Immunology). Most Siglecs contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic domains, which mediate inhibitory signaling to prevent overactive immune responses and maintain self-tolerance (Duan, S., & Paulson, J. C., 2020, Annual Review of Immunology). In oncology, tumors often exploit this pathway by overexpressing sialic acids, which engage Siglecs on immune cells to create an immunosuppressive environment, effectively acting as glyco-immune checkpoints (Macauley, M. S., et al., 2014, Nature Reviews Immunology). Therapeutic targeting of Siglecs has been successful in hematological malignancies, with drugs like Gemtuzumab ozogamicin targeting Siglec-3 (CD33) and Inotuzumab ozogamicin targeting Siglec-2 (CD22) to deliver cytotoxic payloads (FDA, 2017). Current research is expanding into solid tumors with Siglec-15 inhibitors and into neurodegenerative diseases like Alzheimer's, where Siglec-3 (CD33) is implicated in microglial dysfunction (Griciuc, A., et al., 2013, Neuron).

Other names

SiglecsSialic acid-binding Ig-like lectinsI-type lectinsSialoadhesin familyCD33-related Siglecs

Siglecs are targeted primarily through antibody-drug conjugates (ADCs) that deliver cytotoxic agents upon receptor-mediated endocytosis, and monoclonal antibodies that block inhibitory signaling to restore immune cell activity (checkpoint inhibition).