NKG2D ligands (MICA, MICB, ULBP1-6) (NKG2DLs)

Stress-induced ligands on tumor cells, primarily the NKG2D ligands (MICA, MICB, and ULBP1-6), are a group of cell surface proteins that are upregulated in response to cellular stress, DNA damage, and oncogenic transformation. These ligands are recognized by the activating receptor NKG2D, which is expressed on natural killer (NK) cells, CD8+ T cells, and gamma-delta T cells. Under normal conditions, these ligands are minimally expressed, but their presence on tumor cells serves as a "kill me" signal that triggers immune-mediated destruction. However, tumors often evade this surveillance by shedding these ligands into a soluble form (sNKG2DL), which acts as a decoy and downregulates the NKG2D receptor on effector cells. Related NK-activating ligands include B7-H6 (ligand for NKp30) and PVR/CD155 (ligand for DNAM-1), which similarly signal the presence of transformed cells. Therapeutic strategies targeting this axis include NKG2D-based CAR-T cells, monoclonal antibodies that stabilize surface ligands or prevent shedding, and small molecules like HDAC inhibitors that induce ligand expression. These approaches aim to restore or enhance the innate and adaptive immune response against a wide variety of solid and hematological malignancies.

Other names

Stress-induced ligandsMHC class I polypeptide-related sequence A/BUL16-binding proteinsRAET1 familyNK-activating receptor ligandsMICAMICBULBP1ULBP2ULBP3ULBP4ULBP5ULBP6B7-H6PVRCD155

Drugs targeting these ligands primarily work by activating NK cells and T cells through the NKG2D receptor, preventing the proteolytic shedding of ligands from the tumor surface, or inducing the expression of these ligands using stress-mimicking agents like HDAC inhibitors.