Natural killer cell receptor system (NKG2D and KIR) (NKRs)

The Natural killer (NK) cell receptor system is a complex network of activating and inhibitory receptors that mediate the recognition of malignant cells (Vivier et al., Science 2011). This system primarily involves the recognition of "stress-induced" ligands, such as MICA and MICB, by the activating receptor NKG2D (KLRK1), and the "missing-self" mechanism, where the absence of Major Histocompatibility Complex (MHC) class I molecules triggers NK cell activation by relieving inhibition from Killer-cell Immunoglobulin-like Receptors (KIRs) (Shimasaki et al., Nat Rev Drug Discov 2020). These interactions are central to the Reactome pathway "Cancer-cell-associated stress and 'missing-self' ligands recognized by autologous NK/NKT cell receptors" (R-HSA-1236394). In cancer, the balance of these signals is often disrupted, allowing tumors to evade immune surveillance despite the presence of stress ligands. Therapeutic interventions like monalizumab and lirilumab target these pathways by blocking inhibitory receptors (NKG2A and KIR, respectively) to restore NK cell effector functions (André et al., Cell 2018). Additionally, NKG2D-based chimeric antigen receptor (CAR) therapies are being developed to exploit the broad expression of stress ligands on various solid and hematological tumors. Clinical challenges include the shedding of soluble ligands by tumor cells, which can act as decoys and impair receptor function, and the potential for autoimmune-like toxicities. Monitoring biomarkers such as HLA expression and ligand density is crucial for patient selection in these immunotherapies.

Other names

Cancer-cell-associated stress and 'missing-self' ligands recognized by autologous NK/NKT cell receptorsNK cell activating and inhibitory receptorsNKG2D-MICA/B axisKIR-HLA axisMissing-self recognition systemReactome Pathway R-HSA-1236394

Enhancement of NK cell-mediated tumor lysis by blocking inhibitory checkpoints (KIR, NKG2A) or activating through stress-ligand recognition (NKG2D).