Sialic acid-binding immunoglobulin-like lectin family (SIGLEC) (SIGLEC)

The Sialic acid-binding immunoglobulin-like lectin (Siglec) family is a group of cell-surface transmembrane receptors primarily expressed on immune cells that recognize sialic acid-containing glycans [1, 7]. These receptors function as critical immunomodulators, typically acting as inhibitory checkpoints through immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that help the immune system distinguish "self" from "non-self" by sensing host-specific sialylation patterns [4, 9]. In oncology, many Siglecs are overexpressed on malignant cells, such as CD33 in acute myeloid leukemia and CD22 in B-cell lymphomas, or are utilized by tumors to evade immune surveillance via the "sialoglycan-Siglec axis" [2, 6, 13]. This has led to the successful development of antibody-drug conjugates (ADCs) like Gemtuzumab ozogamicin and Inotuzumab ozogamicin, which exploit the rapid endocytic properties of Siglecs to deliver cytotoxic payloads [1, 12]. Beyond cancer, Siglecs are implicated in neurodegenerative diseases like Alzheimer's, where CD33 and Siglec-11 regulate microglial phagocytosis of amyloid-beta [7, 14]. They also play key roles in inflammatory conditions, such as Siglec-8 in asthma and allergy, and in autoimmune disorders like systemic lupus erythematosus [7, 11]. Current therapeutic strategies include monoclonal antibodies for cell depletion, checkpoint blockade to restore anti-tumor immunity, and glycan-based mimetics to modulate immune signaling [1, 5].

Other names

CD33-related SiglecsI-type lectinsSialic acid-binding Ig-like lectinsSialic acid-binding immunoglobulin-type lectins

Siglec-targeting therapeutics primarily utilize antibody-drug conjugates (ADCs) to deliver cytotoxic agents via receptor-mediated endocytosis, immune checkpoint blockade to disrupt inhibitory sialoglycan-Siglec signaling and restore anti-tumor immunity, and direct induction of apoptosis or depletion of specific immune cell subsets [1, 5, 6].