Tumor ligands for Natural Killer cell activating receptors (NKR-L)

Tumor ligands for Natural Killer (NK) cell activating receptors are a diverse group of proteins expressed on the surface of transformed or stressed cells that trigger NK cell-mediated cytotoxicity (PMID: 21730140). Key examples include the MHC class I polypeptide-related sequence A and B (MICA/B) and UL16-binding proteins (ULBPs), which bind to the NKG2D receptor, as well as B7-H6, which binds to NKp30 (PMID: 19465914). Under normal physiological conditions, these ligands are typically absent or expressed at low levels, but they become upregulated in response to DNA damage, oxidative stress, or oncogenic transformation (PMID: 11777960). In the context of cancer, tumors often develop mechanisms to evade detection by shedding these ligands from their surface via proteolytic cleavage, creating soluble decoys that inhibit NK cell function (PMID: 12446779). Therapeutic strategies targeting these ligands include monoclonal antibodies designed to prevent shedding, bispecific engagers that link ligands to NK receptors, and CAR-T or CAR-NK cells engineered to recognize these stress-induced proteins (PMID: 31110339). By restoring or enhancing the recognition of these ligands, clinicians aim to overcome tumor immune evasion and promote robust anti-tumor immunity.

Other names

NKG2D ligandsNKG2DLStress-induced ligandsMHC class I-related sequence A and BMICA/BUL16-binding proteinsULBPB7-H6PVR/CD155Nectin-2/CD112

Drugs targeting these ligands function by upregulating their surface expression on tumor cells to enhance NK cell recognition, inhibiting proteolytic shedding to prevent the formation of soluble decoys, or utilizing the ligands as binding sites for CAR-T/NK cells and bispecific engagers to direct cytotoxicity.