Natural killer cell receptor-ligand axis (NKRL axis)

The Natural killer (NK) cell receptor-ligand axis is a sophisticated immune surveillance system that regulates NK cell activation through a balance of inhibitory and activating signals. Inhibitory receptors, including Killer-cell Immunoglobulin-like Receptors (KIRs) and the CD94/NKG2A complex, recognize classical and non-classical MHC Class I molecules (HLA-A, -B, -C, and HLA-E) to maintain self-tolerance and prevent autoimmunity [1][2]. Conversely, activating receptors such as NKG2D recognize "stress ligands" like MICA, MICB, and ULBPs, which are typically absent on healthy cells but upregulated during malignant transformation or viral infection [3]. In many cancers, tumor cells evade this surveillance by downregulating MHC molecules (the "missing self" hypothesis) or by shedding stress ligands into the microenvironment to desensitize NK cells [4]. Therapeutic strategies targeting this axis include monoclonal antibodies like Monalizumab (targeting NKG2A) and Lirilumab (targeting KIRs) to block inhibitory checkpoints, as well as NKG2D-based CAR-T/NK cells and bispecific antibodies designed to enhance the recognition of stress-induced ligands on tumor surfaces [5][6].

Other names

Altered MHC and stress ligands recognized by NK-cell receptorsNKG2D-MICA/B axisKIR-HLA axisNK cell checkpoint systemStress-induced ligand recognition pathway

Modulation of NK cell activity by blocking inhibitory receptors (e.g., NKG2A, KIR) or targeting activating receptors (e.g., NKG2D) and their ligands (e.g., MICA/B) to restore anti-tumor immunity.