KIR2DS2 is an activating killer cell immunoglobulin-like receptor expressed on natural killer (NK) cells that recognizes HLA-C1 alleles and selected viral/tumor peptides to enhance NK cell-mediated cytotoxicity 1. Unlike inhibitory KIRs, KIR2DS2 contains a short cytoplasmic tail that promotes NK cell activation rather than inhibition 2. Structurally, KIR2DS2 binds HLA-C*0102 through a conserved 'AT' peptide motif, with critical tyrosine residues distinguishing its activation function from inhibitory homologs 1. KIR2DS2+ NK cells exhibit enhanced spontaneous cytotoxicity against hematological and solid malignancies, including lymphoma and hepatocellular carcinoma, with increased CD16 surface expression and elevated NK-mediated cytotoxicity gene pathways 3. The receptor recognizes peptides from hepatitis C virus and flaviviruses presented by HLA-C 1, and recently was identified to recognize XPO1-derived peptides from tumor cells 4. Clinically, KIR2DS2 presence is associated with reduced hematological malignancy relapse post-transplant and improved solid tumor outcomes 3. However, KIR2DS2 co-inheritance with KIR2DL2 predisposes to symptomatic HSV-1 infection 5, suggesting context-dependent pathogenic versus protective roles. KIR2DS2 marks NK cells primed for anticancer activity and represents a promising target for NK cell immunotherapy strategies.