NKG2D ligand (NKG2DL) (NKG2DL)

NKG2D ligands (NKG2DL), including MICA, MICB, and the ULBP family (ULBP1-6), are cell surface glycoproteins that serve as critical danger signals for the innate immune system. While generally absent from healthy tissues, these ligands are upregulated in tumor cells and cancer stem cells (CSCs) in response to DNA damage, oxidative stress, or oncogenic transformation (PMID: 11777960). They are recognized by the NKG2D activating receptor (KLRK1) on Natural Killer (NK) cells and certain T cell subsets, which triggers the cytotoxic destruction of the ligand-expressing cell (PMID: 29305550). Many cancers downregulate MHC class I to evade CD8+ T-cell recognition, but they often remain susceptible to NK-cell surveillance via the NKG2D-NKG2DL axis (PMID: 31434705). Therapeutic strategies targeting these ligands include CAR-NK and CAR-T cells (e.g., NKX101, CYAD-01) and monoclonal antibodies (e.g., BMS-986390) that aim to prevent the proteolytic shedding of MICA/B, a common immune evasion mechanism where tumors release soluble ligands to act as decoys (PMID: 29590616).

Other names

MICAMICBULBP1-6RAET1Stress-induced ligandsMHC class I polypeptide-related sequence A/B

Binding to the NKG2D (KLRK1) receptor on Natural Killer (NK) cells and cytotoxic T cells to trigger perforin/granzyme-mediated cytolysis of the ligand-expressing cell.