Tumor-associated ligands for NK cell activating receptors

Tumor-associated ligands for NK cell activating receptors are a diverse group of proteins that are upregulated on the surface of cells in response to malignant transformation, viral infection, or cellular stress. These ligands include the MHC class I-related chain A and B (MICA/B), the UL16-binding protein (ULBP) family, B7-H6, and nectin-like proteins such as CD155 and CD112. They serve as critical "danger signals" recognized by activating receptors on natural killer (NK) cells and certain T cell subsets, including NKG2D, NKp30, and DNAM-1. Upon engagement, these ligands trigger potent cytotoxic responses and the secretion of pro-inflammatory cytokines, facilitating the immune-mediated destruction of abnormal cells. However, tumors frequently evade this surveillance by proteolytically shedding these ligands from the cell surface, creating soluble forms that can block receptor function and induce receptor internalization. Therapeutic strategies targeting these ligands include monoclonal antibodies designed to stabilize surface expression and induce antibody-dependent cellular cytotoxicity (ADCC), as well as chimeric antigen receptor (CAR) therapies, such as NKG2D-CAR T cells, which are engineered to recognize the broad array of stress-induced ligands present on various tumor types.

Other names

NKG2D ligandsNatural cytotoxicity receptor ligandsNCR ligandsDNAM-1 ligandsStress-induced ligandsMHC class I-related chain A and B (MICA/B)UL16-binding proteins (ULBPs)B7-H6CD155 (PVR)CD112 (Nectin-2)

Activation of NK cell-mediated cytotoxicity through binding to activating receptors (e.g., NKG2D, NKp30, DNAM-1), induction of antibody-dependent cellular cytotoxicity (ADCC) or phagocytosis (ADCP), and prevention of ligand shedding to restore immune surveillance and receptor expression on effector cells.