Natural killer cell activating receptor ligands (NKp30, NKp44, and DNAM-1 ligands)

The tumor cell ligands for NKp30, NKp44, and DNAM-1 are a diverse group of stress-induced and tumor-associated proteins that serve as critical 'danger signals' for Natural Killer (NK) cell recognition. Key members include B7-H6 and BAG6 (for NKp30), MLL5 and PCNA (for NKp44), and CD155 and CD112 (for DNAM-1). These ligands are typically upregulated on malignant cells in response to oncogenic stress, genomic instability, or viral infection, while remaining largely absent in healthy tissues. While most of these interactions promote NK cell-mediated lysis, certain ligands like membrane-associated PCNA can paradoxically inhibit NK cell activity, functioning as an innate immune checkpoint. Tumors often evade immune detection by shedding these ligands into soluble forms that act as decoys or by downregulating their surface expression. Therapeutic strategies targeting this axis include bispecific engagers like BI 765049, checkpoint-blocking antibodies such as mAb 14-25-9, and pharmacological agents like HDAC inhibitors that induce ligand expression to sensitize tumors to innate immune attack.

Other names

NCR ligandsDNAM-1 ligandsB7-H6 (NCR3LG1)BAG6 (BAT3)MLL5 (Mixed-lineage leukemia 5)PCNA (Proliferating cell nuclear antigen)CD155 (PVR)CD112 (Nectin-2)Galectin-3HLA-DP

These ligands interact with activating receptors (NKp30, NKp44, and DNAM-1) on Natural Killer (NK) cells to trigger cytotoxicity and cytokine production; therapeutic agents either directly engage these ligands to redirect immune cells or pharmacologically upregulate their expression to enhance tumor immunogenicity.