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

Killer cell lectin-like receptor subfamily K member 1 (NKG2D) is a type II transmembrane protein and a potent activating receptor primarily expressed on natural killer (NK) cells, CD8+ T cells, and γδ T cells [1, 13]. It recognizes a diverse set of stress-induced ligands, including MHC class I polypeptide-related sequences A and B (MICA and MICB) and UL16-binding proteins (ULBP1-6), which are upregulated on cells undergoing malignant transformation, viral infection, or DNA damage [8, 14]. In healthy individuals, these ligands are largely absent, making the NKG2D-ligand axis a critical component of the induced-self recognition system for tumor immunosurveillance [2, 12]. However, tumors frequently employ evasion strategies, such as the proteolytic shedding of ligands (e.g., soluble MICA), which leads to receptor internalization and systemic immune suppression [15, 17]. Therapeutic interventions targeting this axis include NKG2D-based chimeric antigen receptor (CAR) T and NK cells, bispecific engagers that link NKG2D to tumor antigens, and monoclonal antibodies designed to prevent ligand shedding or block the receptor in autoimmune contexts [4, 8, 11]. While promising, these therapies face challenges such as potential off-tumor toxicity in tissues with low-level ligand expression and the complex regulatory environment of the tumor microenvironment [3, 18].

Other names

CD314KLRK1NKG2-DNatural killer group 2 member DMHC class I polypeptide-related sequence A (MICA)MHC class I polypeptide-related sequence B (MICB)UL16-binding proteins (ULBP1-6)RAET1ERAET1GRAET1HRAET1LRAET1NNKG2D-NKG2DL axis

NKG2D-targeted therapies employ several mechanisms: agonists and CAR-T cells (e.g., CYAD-01) activate NK and T cells to kill ligand-expressing tumor cells; bispecific engagers (e.g., DF1001) bridge immune cells to tumors; and monoclonal antibodies (e.g., JNJ-64304500) block the receptor to treat autoimmune diseases like Crohn's. Additionally, some strategies aim to prevent the shedding of MICA/B or upregulate ligand expression using HDAC inhibitors [3, 4, 8, 11].