KIR2DL4 is an atypical NK cell receptor that recognizes HLA-G, a non-classical MHC class Ib molecule, playing critical roles in both immune tolerance and anti-tumor immunity. Unlike conventional KIR receptors, KIR2DL4 contains both activation (ARAM) and inhibition (ITIM) motifs, enabling context-dependent signaling 1. At the maternal-fetal interface, KIR2DL4 engagement with HLA-G on decidual NK cells triggers senescence-associated secretory phenotype, promoting vascular remodeling and fetal growth while maintaining immune tolerance [UniProt]. Upon HLA-G binding, KIR2DL4 initiates endosomal signaling activating PRKDC-XRCC5 and AKT1, leading to NF-κB-dependent pro-inflammatory responses [UniProt]. In cancer, KIR2DL4 emerges as a pivotal immune checkpoint molecule. HLA-G/KIR2DL4 interaction suppresses NK cell cytotoxicity and antibody-dependent cell-mediated cytotoxicity against HER2-positive breast cancer, promoting trastuzumab resistance through excessive TGF-β and IFN-γ production 2. Elevated KIR2DL4 expression occurs in melanoma, lung, and ovarian cancers, supporting its role in tumor immune evasion 3. Conversely, KIR2DL4 upregulation activates MEK/ERK signaling in NK cells, enhancing anti-tumor cytotoxicity and cytokine secretion 4. Genetic polymorphisms in KIR2DL4 and HLA-G associate with pregnancy outcomes and infectious disease susceptibility, including HCV infection and anti-NMDAR encephalitis 5, 6, 7. KIR2DL4 blockade represents a promising therapeutic strategy to overcome immune escape in HLA-G-expressing cancers.