Sialic acid-binding Ig-like lectin (Siglec) (Siglec)

Sialic acid-binding Ig-like lectins (Siglecs) are a family of type I transmembrane proteins that function as cell surface receptors, primarily on hematopoietic cells, to recognize sialic acid-containing glycans (UniProt). Most members of this family, such as Siglec-2 (CD22) and Siglec-3 (CD33), contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic tails, which recruit phosphatases like SHP-1 and SHP-2 to dampen immune cell activation (PubMed: 24388214). This inhibitory function is crucial for maintaining self-tolerance and preventing excessive inflammation. In many cancers, the upregulation of sialic acids on the tumor cell surface allows the tumor to exploit Siglec signaling to evade immune detection, leading to the classification of Siglecs as "glyco-immune checkpoints" (PubMed: 30612032). Therapeutic interventions targeting Siglecs include antibody-drug conjugates (ADCs) like Gemtuzumab ozogamicin for leukemia and blocking antibodies currently in clinical trials for solid tumors (NIH: NCT03665285). Beyond oncology, Siglecs are being investigated for their roles in neurodegeneration, where specific variants are associated with the risk of Alzheimer's disease. Overall, the Siglec family represents a diverse set of therapeutic targets for modulating immune responses across various disease states.

Other names

Sialic acid-binding immunoglobulin-type lectinI-type lectinSiglecsCD22CD33Siglec-15

Siglecs are targeted primarily through antibody-drug conjugates (ADCs) that deliver cytotoxic payloads to specific immune or malignant cells, or via monoclonal antibodies that block inhibitory signaling (checkpoint inhibition) to enhance anti-tumor immune responses.