Natural killer cell lectin-like receptor subfamily K member 1 (NKG2D) and its ligands (NKG2D/NKG2DL)

The Natural killer cell lectin-like receptor subfamily K member 1 (NKG2D) is a major activating receptor found on natural killer (NK) cells, CD8+ T cells, and gamma-delta T cells [1]. Its ligands, which include MICA, MICB, and the ULBP family, are stress-induced proteins that are typically absent from healthy cells but highly expressed on the surface of various cancers, including hepatocellular carcinoma (HCC) [2]. The interaction between NKG2D and its ligands serves as a critical danger signal that triggers the innate and adaptive immune systems to eliminate transformed cells [3]. In therapeutic contexts such as Vax-NK, autologous NK cells are expanded and activated ex vivo to enhance their NKG2D-mediated recognition of tumor cells [4]. Once infused, these cells bind to NKG2D ligands on HCC cells, inducing targeted cell death through the secretion of cytotoxic granules containing perforin and granzymes [5]. However, tumors often evade this response by shedding surface ligands into a soluble form, which acts as a decoy and downregulates NKG2D expression on immune cells [6]. Current research focuses on overcoming this evasion and optimizing the NKG2D-ligand axis for more effective cancer immunotherapy [7].

Other names

KLRK1CD314MHC class I polypeptide-related sequence A (MICA)MHC class I polypeptide-related sequence B (MICB)UL16-binding proteins (ULBPs)RAET1

Activation of NK cell cytotoxicity through the binding of the NKG2D receptor to stress-induced ligands (MICA/B, ULBPs) on the surface of tumor cells, leading to the release of perforin and granzymes.