CLEC12A is a myeloid inhibitory C-type lectin receptor that suppresses immune cell activation through recognition of danger-associated and pathogen-associated molecules. The receptor binds neutrophil extracellular traps (NETs), monosodium urate crystals, and microbial ligands such as plasmodium hemozoin and mycobacterial micolic acid. Upon ligand binding, CLEC12A undergoes phosphorylation of its ITIM motif, recruiting protein tyrosine phosphatases PTPN6 and PTPN11 that antagonize SYK kinase signaling, thereby preventing myeloid cell activation. CLEC12A also inhibits natural killer cell cytotoxicity and suppresses dendritic cell maturation in an IL10-dependent manner, collectively limiting excessive inflammation and NET-mediated tissue damage. CLEC12A is preferentially expressed on acute myeloid leukemia (AML) blasts and leukemic stem cells while absent from normal hematopoietic stem and progenitor cells, making it an attractive immunotherapy target. Low CLEC12A expression on leukemic blasts is independently associated with lower complete remission rates, shorter event-free survival, and overall survival in AML 1. CLEC12A is required for pathogenesis in NUP98::NSD1 AML, where depletion significantly reduces leukemic engraftment and prolongs survival in murine models 2. Multiple CAR-T cell strategies targeting CLEC12A alone or in combination with ADGRE2 have entered clinical evaluation, with cooperative targeting approaches demonstrating selective AML eradication while minimizing normal hematopoietic toxicity 34. Dysregulated CLEC12A expression also associates with autoimmune and inflammatory diseases, including rheumatoid arthritis, lupus, and gout.