Zhang Xiaolong, Yin Zheng, Wu Jie, Xiang Xiao, Zou Dawei, Wang Guangchuan, Fu Jinfei, Lan Peixiang, Minze Laurie J, Li Xian C, Chen Wenhao
Department of Surgery, Immunobiology and Transplant Science Center, Houston Methodist Research Institute and Institute for Academic Medicine, Houston Methodist Hospital, Houston, TX, USA.
Department of Systems Medicine and Bioengineering, Houston Methodist Neal Cancer Center, Houston, TX, USA.
Nat Immunol. 2025 Jun 16. doi: 10.1038/s41590-025-02176-w.
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 CD27CD24 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.
自然杀伤（NK）细胞对于控制肿瘤转移至关重要，但其进入耗竭状态时保护能力会减弱。NK细胞耗竭的潜在机制尚未完全明确。在此，我们表明NK细胞对耗竭的易感性在其发育早期就已预先确定，并受转录因子IRF4调控。值得注意的是，IRF4在CD27CD24 NK前体细胞中高表达，但在未成熟和成熟NK细胞中几乎不存在。删除IRF4会改变NK细胞的发育方向，使NK前体细胞产生更多抗耗竭的成熟NK细胞，从而减少黑色素瘤肺转移。效应分子产生增加以及抑制性受体如TIGIT和Pik3ip1表达降低表明了这种对耗竭的抗性。删除Pik3ip1也增强了NK细胞对抗黑色素瘤肺转移的能力。这些发现加深了我们对NK细胞耗竭的理解，并对利用NK细胞预防癌症转移具有启示意义。
