Natural killer cell activating and inhibitory receptors (NKRs) (NKRs)

Natural killer (NK) cell activating and inhibitory receptors are a complex system of surface proteins that regulate the innate immune response against abnormal host cells. Inhibitory receptors, including Killer-cell Immunoglobulin-like Receptors (KIRs) and the CD94/NKG2A heterodimer, recognize self-MHC class I molecules to maintain self-tolerance and prevent autoimmunity (Long et al., 2013, Immunity). Activating receptors, such as NKG2D and the natural cytotoxicity receptors (NKp30, NKp44, NKp46), identify ligands associated with cellular stress, viral infection, or malignant transformation (Vivier et al., 2011, Science). In many cancers, the balance of these signals is disrupted, allowing tumor cells to evade immune detection by overexpressing inhibitory ligands or downregulating activating ones. Therapeutic strategies currently under investigation include monoclonal antibodies that block inhibitory checkpoints and chimeric antigen receptor (CAR) constructs that utilize activating receptor domains to redirect NK cells toward tumor targets (Shimasaki et al., 2020, Nature Reviews Drug Discovery). These approaches aim to restore the natural surveillance capacity of the innate immune system to eliminate resistant malignancies. Drugs like monalizumab and lirilumab are prominent examples of agents designed to tip the balance toward NK cell activation in the clinical setting (André et al., 2018, Cell).

Other names

NK cell receptorsActivating and inhibitory NK receptorsNK cell checkpointsNatural killer cell surface receptors

Therapeutic agents modulate NK cell activity by either blocking inhibitory receptors (e.g., KIR, NKG2A) to prevent 'off' signals from tumor cells or by stimulating activating receptors (e.g., NKG2D, NKp46) to trigger direct cytotoxicity (Vivier et al., 2012, Nature). This 'checkpoint' modulation or direct engagement via bispecific antibodies (BiKEs) allows NK cells to overcome tumor-induced immunosuppression and effectively lyse stressed or malignant cells (Shimasaki et al., 2020, Nature Reviews Drug Discovery).