Natural cytotoxicity trigger receptor 1 (NKp46)

Natural cytotoxicity trigger receptor 1 (NCR1), widely known as NKp46, is a type I transmembrane glycoprotein and a primary activating receptor expressed constitutively on all mature Natural Killer (NK) cells and a subset of T cells [1][2]. It belongs to the immunoglobulin superfamily and plays a pivotal role in the innate immune system by identifying and eliminating virally infected or transformed cells [3]. NKp46 recognizes diverse ligands, including viral hemagglutinins from influenza and Sendai viruses, bacterial components, and various uncharacterized ligands upregulated on tumor cells [4][5]. Upon ligand binding, NKp46 signals through ITAM-containing adapter proteins like CD3-zeta and Fc-epsilon-RI-gamma to trigger calcium mobilization, degranulation, and the production of pro-inflammatory cytokines such as IFN-gamma [1][6]. In modern oncology, NKp46 is a high-priority therapeutic target for the development of multi-specific NK-cell engagers (e.g., ANKETs), which aim to harness the potent anti-tumor activity of NK cells while potentially offering a better safety profile than T-cell-directed therapies [7]. Additionally, NKp46 has been implicated in the development of type 1 diabetes, where it may recognize ligands on pancreatic beta cells, suggesting its relevance beyond cancer immunotherapy [8].

Other names

NCR1CD335Lymphocyte antigen 94 homologLY94Natural killer cell p46-related protein

Targeting through multi-specific Natural Killer (NK) cell engagers that cross-link NKp46 on NK cells with tumor-associated antigens to trigger targeted cytotoxicity and cytokine release.