Natural Killer Group 2 Member D ligands (NKG2DL)

Natural Killer Group 2 Member D (NKG2D) ligands, primarily comprising MHC class I polypeptide-related sequence A (MICA), MICB, and the UL16-binding protein (ULBP) family, are stress-induced proteins that act as critical recognition signals for the innate and adaptive immune systems (Duan et al., 2019, Frontiers in Immunology). These ligands are typically absent from healthy tissues but are highly expressed on the surface of cells undergoing malignant transformation, viral infection, or oxidative stress (Lanier, 2015, Nature Reviews Cancer). Upon binding to the NKG2D receptor on NK cells and cytotoxic T cells, they trigger the release of perforin and granzymes, leading to the lysis of the target cell (Zingoni et al., 2018, Frontiers in Immunology). Related immune-activating systems include the DNAM-1 receptor and its ligands (CD155/CD112) and the NKp30 receptor and its ligand B7-H6, which collectively coordinate innate tumor surveillance. In many cancers, the therapeutic potential of this axis is hampered by 'shedding,' where proteolytic cleavage releases soluble ligands that act as decoys, systemically downregulating NKG2D expression and facilitating immune escape (Ferrari de Andrade et al., 2018, Science). Current drug development efforts focus on monoclonal antibodies that block this shedding, bispecific engagers that redirect immune cells to NKG2DL-positive tumors, and CAR-T cells (such as CYAD-01) engineered with the NKG2D extracellular domain to recognize the broad array of ligands presented by various tumor types (Sallman et al., 2023, Journal of Clinical Oncology).

Other names

MHC class I polypeptide-related sequence AMHC class I polypeptide-related sequence BMICAMICBUL16-binding proteinsULBP1ULBP2ULBP3ULBP4ULBP5ULBP6RAET1B7-H6CD155CD112Stress-induced ligands

Activation of NKG2D-mediated cytotoxicity and prevention of ligand shedding from the tumor cell surface.