NKG2D ligands (Natural killer group 2 member D ligands) (NKG2DL)

NKG2D ligands (NKG2DL) are a group of cell surface proteins, including MICA, MICB, and the ULBP family (ULBP1-6), that are typically absent or expressed at very low levels on healthy cells but become highly upregulated in response to cellular stress, DNA damage, or malignant transformation. These ligands act as critical 'danger signals' that are recognized by the NKG2D activating receptor found on Natural Killer (NK) cells, CD8+ T cells, and γδ T cells, thereby facilitating the immune-mediated destruction of compromised cells (Source: PMID: 21844392, UniProt P43622). In oncology, the overexpression of these ligands on tumor cells makes them attractive targets for immunotherapy, particularly for Chimeric Antigen Receptor (CAR) T-cell therapies and bispecific engagers. However, many tumors have evolved mechanisms to evade this recognition, such as the proteolytic shedding of these ligands into a soluble form (sMICA/B), which can desensitize immune cells and act as a decoy (Source: PMID: 12192402). Current drug development efforts focus on targeting the membrane-bound forms of these ligands or preventing their shedding to restore effective anti-tumor immunity (Source: PMID: 30206130).

Other names

Stress-induced ligandsMICA/BUL16-binding proteinsULBPsRAET1 proteinsMHC class I polypeptide-related sequence A and B

Therapeutic agents, such as CAR-T cells or bispecific antibodies, are engineered to recognize and bind to NKG2D ligands (MICA/B, ULBPs) expressed on the surface of tumor cells. This binding triggers the activation of the effector immune cells (e.g., T cells or NK cells), leading to the release of perforins and granzymes that induce apoptosis and lysis of the target tumor cell (Source: PMID: 29653964, PMID: 31434694).