Natural cytotoxicity triggering receptor 1 (NKp46) (NKp46)

Natural cytotoxicity triggering receptor 1, commonly known as NKp46 or CD335, is a major activating receptor expressed almost exclusively on natural killer (NK) cells and a small subset of T cells. It plays a pivotal role in the innate immune system's ability to detect and eliminate virally infected cells and tumor cells by recognizing a broad range of ligands, including viral hemagglutinins and various stress-induced or tumor-associated molecules. Upon engagement, NKp46 signals through its association with ITAM-containing adapter proteins, such as CD3-zeta and Fc-epsilon-RI-gamma, to trigger potent cytolytic activity and cytokine secretion. In modern oncology, NKp46 is a high-priority therapeutic target for the development of multi-specific NK cell engagers (NKCEs). These agents are designed to bridge allogeneic or endogenous NK cells to malignant cells, facilitating targeted destruction of tumors while potentially minimizing the severe toxicities often associated with T-cell-directed therapies.

Other names

NCR1CD335LY94Natural killer cell p46-related proteinLymphocyte antigen 94 homolog

NKp46 acts as a primary activating receptor on natural killer (NK) cells. Therapeutic strategies involve using bispecific or trispecific NK cell engagers (NKCEs) that simultaneously bind NKp46 and CD16 on NK cells and a specific antigen on tumor cells. This multi-valent engagement triggers NK cell activation, degranulation, and the release of cytotoxic perforins and granzymes, leading to the targeted lysis of tumor cells (antibody-dependent cellular cytotoxicity-like mechanism).