B7 homolog 6 (B7-H6), encoded by the NCR3LG1 gene in humans, is a type I transmembrane glycoprotein and a member of the B7 family of immune-regulatory ligands. It contains two extracellular immunoglobulin-like domains and is expressed on the surface of a broad range of tumor cells, including hematological malignancies such as lymphomas and leukemias as well as carcinomas and melanomas, but is essentially absent from healthy normal tissues, being induced by cellular stress and transformation. B7-H6 is the principal cellular ligand for NKp30 (natural cytotoxicity receptor 3, NCR3), an activating immunoreceptor expressed on natural killer (NK) cells. Engagement of NKp30 by membrane-bound B7-H6 triggers NK-cell activation, granule exocytosis, target-cell cytolysis, and secretion of interferon-gamma and TNF, forming a core axis of innate tumor immune surveillance. B7-H6 can also be proteolytically shed from the tumor-cell surface by metalloproteinases, and soluble B7-H6 down-modulates NKp30 on NK cells, contributing to tumor immune escape. B7-H6 is a plasma-membrane receptor-type ligand on tumor cells, with a soluble ectodomain form released into the tumor microenvironment and circulation.