CD33 is a sialic acid-binding immunoglobulin-like lectin (Siglec) expressed on myeloid cells that suppresses immune activation through inhibitory signaling. The receptor preferentially binds alpha-2,3- and alpha-2,6-linked sialic acids on glycoproteins and pathogen-associated ligands. Upon ligand engagement, two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in CD33's cytoplasmic tail are phosphorylated by Src-like kinases, recruiting and activating protein-tyrosine phosphatases PTPN6/SHP-1 and PTPN11/SHP-2, which then dephosphorylate downstream signaling molecules to dampen monocyte activation and cytokine production. CD33 has emerged as a major therapeutic target in acute myeloid leukemia (AML), with multiple CAR-T and CAR-NK cell approaches in clinical development. Approved antibody-drug conjugates targeting CD33, including gemtuzumab ozogamicin and lintuzumab, enable selective delivery of cytotoxic payloads to leukemic blasts 1. Recent clinical-stage advances include drug-regulated CAR T cells (DARIC33) enabling pharmacologic control of antitumor activity 2, dual-targeting approaches combining CD33 with CD70 to overcome antigen escape 3, and allogeneic CAR-NKT cells offering reduced toxicity for bone marrow-resident disease 4. To mitigate on-target, off-tumor myelotoxicity, CD33 genetic inactivation in autologous hematopoietic stem cells enables AML-specific targeting 5. CD33 is also implicated in Alzheimer's disease susceptibility through genetic association studies. The Alzheimer's risk variant increases expression of the full-length CD33 isoform (CD33M) in microglia and alters its interaction with SHP-1 6, potentially impairing microglial clearance of amyloid-β aggregates 7.