Tumor cell ligands for Natural cytotoxicity receptor 1 (NKp46) (NKp46L)

Tumor cell ligands for Natural cytotoxicity receptor 1 (NKp46) are a heterogeneous group of molecules expressed or secreted by malignant cells that serve as activating signals for Natural Killer (NK) cells. NKp46 (also known as CD335) is a key member of the natural cytotoxicity receptor (NCR) family and is constitutively expressed on all mature NK cells, where it plays a primary role in the immunosurveillance of tumors and viral infections [6, 20]. While the identity of these ligands was long considered a holy grail of NK cell biology, several key tumor-associated ligands have been identified, including heparan sulfate proteoglycans (HSPGs), cell-surface vimentin (CSV), externalized calreticulin (ecto-CRT), and complement factor P (properdin) [1, 7, 12, 14]. Binding of these ligands to the extracellular domains of NKp46 triggers intracellular signaling through ITAM-containing adapter proteins like CD3ζ and FcεRIγ, leading to NK cell degranulation, cytokine release (such as IFN-γ and TNF-α), and the subsequent lysis of the tumor cell [11, 20]. In the context of cancer, the expression of these ligands is often induced by cellular stress, DNA damage, or the epithelial-mesenchymal transition (EMT), making them critical markers for NK cell-mediated recognition [14, 17]. However, tumors can employ various evasion strategies, such as the shedding of ligands or the downregulation of NKp46 expression on infiltrating NK cells [6, 10]. Therapeutic development in this area focuses on Natural Killer Cell Engagers (NKCEs), which are multi-specific antibodies designed to bypass natural ligand-receptor interactions by directly cross-linking NKp46 to specific tumor-associated antigens [16].

Other names

NKp46 ligandsNCR1 ligandsCD335 ligandsNatural cytotoxicity receptor 1 ligands

NK cell engagement, NKp46 agonism, Ligand-mediated NK cell activation