B7-H6 is a 51 kD type-1 transmembrane protein composed of 454 amino acids, with two immunoglobulin (Ig) domains, an IgC domain, an IgV domain, and a signal peptide. It interacts with NKp30, an activating receptor on natural killer (NK) cells, triggering innate immune responses. B7-H6 is primarily expressed in humans and rats as a surface protein. The surface form of B7-H6 binds to NKp30 expressed on NK cells and induces NK cell activation. In contrast, the soluble form of B7-H6, shed by metalloproteases ADAM-10 and ADAM-17, inhibits NK cell function by inhibiting NKp30 activation. Chronic stimulation of NK cells with the soluble form of B7-H6 can downregulate the cognate receptor of B7-H6, NKp30. B7-H6 expression has been associated with various cancers, including high-risk neuroblastoma, astrocytoma, and glioma. In high-risk neuroblastoma, serum concentrations of soluble B7-H6 are associated with downregulation of NKp30 expression, bone marrow metastasis, and chemoresistance. In astrocytoma, B7-H6 surface expression is associated with the WHO grade but not with survival rates. In glioma, B7-H6 expression is linked to disease progression and is significantly relevant to cancer progression and pathological type.