Natural killer cell activating receptors and ligands (NK cell activating receptors)

Natural killer (NK) cell activating receptors and their corresponding ligands form a critical axis in the innate immune system's ability to detect and eliminate malignant or stressed cells [1, 2]. Key activating receptors include NKG2D (KLRK1), the natural cytotoxicity receptors (NCRs: NKp30, NKp44, NKp46), DNAM-1 (CD226), and CD16 (FcγRIIIa) [3, 7]. These receptors recognize "induced-self" ligands, such as MICA/B, ULBPs, B7-H6, and nectins, which are typically absent or lowly expressed on healthy tissues but upregulated in response to cellular stress, DNA damage, or oncogenic transformation [5, 14]. In the context of cancer, tumors often employ escape mechanisms such as proteolytic shedding of these ligands to act as soluble decoys or downregulating receptor expression via immunosuppressive cytokines like TGF-beta [10, 15]. Therapeutic strategies targeting this axis include bispecific and trispecific NK cell engagers (BiKEs/TriKEs), monoclonal antibodies that prevent ligand shedding, and CAR-NK cell therapies designed to overcome tumor-induced suppression and potently activate NK cell-mediated cytotoxicity and cytokine production [1, 11, 16].

Other names

Activating natural killer cell receptorsKiller activation receptorsKARsNatural cytotoxicity receptorsNCRsNKG2D systemDNAM-1 systemStress-induced ligands

Activation of NK cell cytotoxicity and cytokine production through direct engagement of activating receptors or stabilization of their ligands on target cells to promote immune recognition.