Natural killer cell activating receptors (NKARs) (NKARs)

Natural killer (NK) cell activating receptors are a heterogeneous group of cell surface proteins that mediate the recognition and destruction of stressed, infected, or transformed cells (Vivier et al., 2011). These receptors, which include NKG2D, CD16 (FcγRIIIa), and the natural cytotoxicity receptors (NKp30, NKp44, and NKp46), function by detecting ligands that are often upregulated during cellular stress or viral infection (Long et al., 2013). Upon ligand binding, these receptors signal through ITAM-containing adapter molecules to trigger degranulation and the release of pro-inflammatory cytokines like IFN-gamma (Shimasaki et al., 2020). In the context of cancer, these receptors are critical for immunosurveillance, but tumors often evade detection by shedding ligands or upregulating inhibitory signals (Waldhauer & Steinle, 2008). Therapeutic strategies currently focus on using bispecific or trispecific NK cell engagers (BiKEs/TriKEs) to cross-link these activating receptors with tumor-associated antigens (Demaret et al., 2021). Additionally, CAR-NK cell therapies are being developed to exploit these endogenous activation pathways for enhanced anti-tumor efficacy (Liu et al., 2020). Understanding the balance between these activating signals and inhibitory checkpoints is essential for the development of effective NK-cell-based immunotherapies.

Other names

NK cell activating receptorsNatural cytotoxicity receptorsNCRsActivating NK receptorsNK cell triggers

Activation of NK cell-mediated cytotoxicity and cytokine release through multi-specific engagement or direct receptor stimulation.