NKG2D ligands (NKG2DL) (NKG2DL)

NKG2D ligands (NKG2DLs) are a diverse group of cell surface proteins, primarily comprising MICA, MICB, and the ULBP family (ULBP1-6), that are typically absent or expressed at low levels on healthy cells but are significantly upregulated in response to cellular stress, such as malignant transformation, viral infection, or DNA damage (Schmiedel & Mandelboim, 2018, Frontiers in Immunology). These ligands serve as critical "eat-me" signals for the immune system by binding to the NKG2D activating receptor found on Natural Killer (NK) cells, CD8+ T cells, and certain subsets of γδ T cells, thereby triggering cytotoxic activity and cytokine production (Duan et al., 2019, International Journal of Cancer). In the context of oncology, many solid and hematological tumors overexpress these ligands, making them attractive targets for various immunotherapies, including CAR-T cells (e.g., CYAD-01) and bispecific engagers designed to bridge immune effectors to the tumor (Zingoni et al., 2018, Frontiers in Immunology). However, tumors often employ evasion mechanisms, such as the proteolytic shedding of these ligands into a soluble form (sNKG2DL), which can act as a decoy to desensitize immune cells and facilitate immune escape (UniProt Q29983). Therapeutic strategies currently under investigation aim to either target the membrane-bound forms directly, prevent the shedding process via ADAM10/17 inhibition, or use antibodies to stabilize the ligands on the cell surface to restore effective anti-tumor immunity (Ferrari de Andrade et al., 2018, Science).

Other names

MICA/BULBPsStress-induced ligandsRAET1 proteinsMHC class I polypeptide-related sequence A/BUL16-binding proteins

Activation of NKG2D-mediated cytotoxicity, CAR-T cell recognition of stress-induced ligands, and inhibition of proteolytic shedding of MICA/B.