NKG2D ligands and stress-induced NK cell receptor ligands (NKG2DLs)

NKG2D ligands (NKG2DLs), such as MICA, MICB, and the ULBP family, are cell surface proteins that act as critical markers of cellular distress. While largely absent from healthy tissues, these ligands are upregulated in response to DNA damage, viral infection, or oncogenic transformation (UniProt P43359, Q29980). They are recognized by the NKG2D activating receptor found on Natural Killer (NK) cells and various T cell subsets, triggering a potent cytotoxic response to eliminate the compromised cells (Lanier, 2003, PMID: 11491521). In the context of oncology, many tumors evade this immune surveillance by proteolytically shedding these ligands from their surface, creating soluble decoys that desensitize the immune system (Groh et al., 2002, PMID: 12447349). Therapeutic interventions currently in development include monoclonal antibodies designed to block this shedding, bispecific engagers, and CAR-T or CAR-NK cells engineered to target these ligands (Celyad Oncology; Innate Pharma). These strategies aim to restore the immune system's ability to recognize and destroy malignant cells across a broad spectrum of solid and hematologic cancers.

Other names

MHC class I polypeptide-related sequence A (MICA)MHC class I polypeptide-related sequence B (MICB)UL16-binding proteins (ULBP1-6)Retinoic acid early transcript 1 (RAET1) proteinsB7-H6Stress-induced ligandsNK cell activating ligands

Activation of the NKG2D receptor on NK cells and T cells to induce target cell lysis; stabilization of surface ligands by inhibiting proteolytic shedding.