Natural killer cell activating receptors (NKRs)

Natural killer (NK) cell activating receptors are a group of surface proteins, including CD16 (FcγRIIIa), NKG2C, and natural cytotoxicity receptors (NCRs), that trigger the effector functions of NK cells against malignant or infected targets (Schlums et al., 2015, Immunity). In the context of adaptive g-NK cells—a specialized subset lacking the FcεRIγ signaling chain—these receptors exhibit enhanced signaling through the CD3ζ chain, leading to potent anti-tumor activity (Muntasell et al., 2017, Front Immunol). The primary mechanism involves CD16-mediated recognition of the Fc portion of monoclonal antibodies bound to tumor cells, a process known as antibody-dependent cellular cytotoxicity (ADCC) (Wang et al., 2015, Front Immunol). Additionally, these receptors allow g-NK cells to recognize stress-induced ligands on tumor cells independently of antibodies. Therapeutic strategies often involve the use of allogeneic g-NK cells in combination with tumor-targeting antibodies to maximize the immune response against cancers such as non-Hodgkin lymphoma and various solid tumors (Gamida Cell, 2024).

Other names

CD16Fc gamma receptor IIIaNKG2CNatural cytotoxicity receptorsg-NK receptorsActivating NK cell receptors

Monoclonal antibodies bind to tumor antigens and their Fc regions subsequently engage CD16 on g-NK cells to induce antibody-dependent cellular cytotoxicity (ADCC); allogeneic g-NK cells also directly recognize tumor ligands via natural cytotoxicity receptors (NCRs) and NKG2C to induce apoptosis.