IRF4 expression by NK precursors predetermines exhaustion of NK cells during tumor metastasis

Natural killer (NK) cells are essential for controlling tumor metastasis, but their protective capacity diminishes when entering an exhaustion state. The mechanisms underlying NK cell exhaustion are incompletely understood. Here, we show that the susceptibility of NK cells to exhaustion is predetermined early during their development and is governed by the transcription factor IRF4. Notably, IRF4 is highly expressed in CD27⁻CD24⁺ NK precursors but is nearly absent in immature and mature NK cells. Deletion of IRF4 redirects NK cell development, enabling NK precursors to generate more mature NK cells that resist exhaustion, thereby decreasing melanoma lung metastasis. This resistance to exhaustion is evident by increased effector molecule production and decreased expression of inhibitory receptors such as TIGIT and Pik3ip1. Deleting Pik3ip1 also enhances NK cell ability to counteract melanoma lung metastasis. These findings enhance our understanding of NK cell exhaustion and have implications for preventing cancer metastasis using NK cells.