Natural killer group 2 member D (NKG2D) and Low affinity immunoglobulin gamma Fc region receptor III-A (CD16A) (NKG2D/CD16)

The target refers to the primary activation pathways of Natural Killer (NK) cells, specifically the NKG2D (KLRK1) and CD16 (FCGR3A) receptors. NKG2D is a potent activating receptor that recognizes stress-induced ligands such as MICA, MICB, and the ULBP family, which are upregulated on the surface of tumor cells undergoing DNA damage or oncogenic transformation. CD16 is the low-affinity Fc gamma receptor IIIa that mediates antibody-dependent cellular cytotoxicity (ADCC) by binding to the Fc portion of IgG antibodies opsonizing tumor cells. Together, these pathways allow NK cells to identify and eliminate malignant cells through the release of cytotoxic granules containing perforin and granzymes. Therapeutic strategies targeting these receptors include bispecific and trispecific killer engagers (BiKEs and TriKEs), which bridge NK cells to tumor antigens, and CAR-NK cells engineered to express NKG2D or CD16. Challenges in targeting these pathways include the shedding of soluble ligands by tumor cells, which can act as decoys to evade immune detection, and the potential for cytokine release syndrome upon potent NK cell activation. Monitoring biomarkers such as MICA/B expression and CD16 polymorphisms is essential for optimizing patient selection and treatment efficacy in oncology.

Other names

KLRK1FCGR3ACD314CD16NKG2D ligandsMICAMICBULBPFc gamma receptor IIIaStress-induced ligands

Activation of NK cells and cytotoxic T cells through the dual recognition of stress-induced ligands and antibody-opsonized tumor cells, triggering the release of lytic granules and pro-inflammatory cytokines.