CD33 is a sialic acid-binding immunoglobulin-like lectin (Siglec) that functions as an inhibitory receptor on myeloid cells. Structurally, CD33 preferentially recognizes alpha-2,6-linked sialic acids on cell surfaces 1 and mediates cell-cell interactions while maintaining immune cells in a resting state 234. Mechanistically, ligand engagement triggers phosphorylation of two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in CD33's cytoplasmic tail by Src-like kinases, recruiting and activating protein tyrosine phosphatases PTPN6/SHP-1 and PTPN11/SHP-2 56. These phosphatases suppress myeloid cell activation through downstream dephosphorylation events, with PI3K contributing to CD33's repressive effects 4. In disease contexts, CD33 variants associated with Alzheimer's disease alter the expression of full-length CD33 isoforms and impair their interaction with SHP-1 in microglia, potentially contributing to neuroinflammation 78. Clinically, CD33's expression on acute myeloid leukemia cells makes it an attractive immunotherapy target; CD33-targeted CAR-T and CAR-NK cells demonstrate potent antitumor activity 91011. However, CD33's expression on normal myeloid cells necessitates genetic inactivation strategies in hematopoietic stem cells to enable selective leukemia targeting without myelotoxicity 1213.