Natural killer cell p46-related protein ligands (NKp46L) (NKp46L)

NKp46 ligands (NKp46L) represent a diverse group of molecules that bind to and activate the NKp46 receptor (NCR1, CD335), a primary activating receptor constitutively expressed on all natural killer (NK) cells (Sivori et al., 1997). These ligands include viral proteins, most notably the hemagglutinins (HA) of influenza and parainfluenza viruses, which allow NK cells to directly recognize and eliminate infected cells (Mandelboim et al., 2001). Additionally, heparan sulfate (HS) proteoglycans on the surface of target cells serve as essential co-ligands or primary ligands, facilitating the stable interaction between NK cells and their targets (Hecht et al., 2009). In the context of oncology, various tumor-associated ligands are expressed on malignant cells, although many of these remain molecularly uncharacterized; their presence is typically identified by the NKp46-dependent lysis of tumor cell lines (Ghadially et al., 2017). Therapeutic strategies targeting the NKp46-ligand axis primarily involve the development of multi-specific NK cell engagers (NKCEs). These agents, such as SAR443579/IPH6101, are designed to bypass the requirement for natural ligand expression by cross-linking the NKp46 receptor on NK cells directly to specific tumor-associated antigens (TAAs) on cancer cells (Innate Pharma, 2023). This engagement triggers potent NK cell activation, cytokine production, and targeted cytotoxicity. While the heterogeneity of natural NKp46 ligands presents a challenge for direct ligand-targeted therapy, the pathway remains a high-priority target for cancer immunotherapy due to the restricted expression of NKp46 on NK cells and its potent role in tumor immunosurveillance.

Other names

NCR1 ligandsCD335 ligandsViral hemagglutininsHeparan sulfate proteoglycansTumor-associated NKp46 ligands

NK cell engagement and activation via NKp46 receptor binding to induce targeted cytotoxicity