An engineered small ligand activates NK cells and triggers their cytolytic activity

Natural killer (NK) cells are crucial to the immune system, playing a key role in cancer prevention by targeting and lysing tumour cells. Their cytotoxicity is mediated through direct and indirect mechanisms, including the release of cytokines and cytolytic enzymes. NK cells can be activated by specific receptors, including NKp30, which recognize ligands on tumour cells. While previous immunotherapies, such as chimeric antigen receptor NK (CAR-NK) cells and antibody-based therapies, have aimed to leverage the tumour-fighting ability of NK cells, they encounter challenges like high costs, low response rates, and tumour heterogeneity. Small-molecule agents have been proposed as a more cost-effective and accessible alternative to stimulate NK cell activity. This study addresses the challenge of identifying a small-molecule ligand that can specifically engage NKp30 to trigger NK-mediated anti-tumour activity. Here, we show that NK815A activates NK cells through NKp30, enhancing cytokine production and promoting degranulation, which lead to increased cytotoxic activity against target cells. Traditionally, NK cell activation has relied on complex and costly bi- and tri-specific engagers or CAR-NK therapies. NK815A provides a simpler, more cost-effective means of activating NK cells, offering a promising alternative to current immunotherapies. These findings suggest that small-molecule ligands offer a viable and scalable strategy for inducing NK cell-mediated cytotoxicity in cancer therapy, enhancing the availability of NK cell-based immunotherapies, and potentially improving prognosis for cancers that respond poorly to conventional treatments.