休斯顿卫理公会医院研究团队取得一项新突破。他们揭示了NK前体表达IRF4预先决定了肿瘤转移过程中NK细胞的衰竭。该项研究成果发表在2025年6月16日出版的《自然—免疫学》上。

小组发现NK细胞对衰竭的易感性在发育早期就已确定，并由转录因子IRF4控制。值得注意的是，IRF4在CD27^-CD24⁺ NK前体，但在未成熟和成熟NK细胞中几乎不存在。IRF4的缺失重定向NK细胞的发育，使NK前体产生更成熟的NK细胞，抵抗衰竭，从而减少黑色素瘤肺转移。这种对衰竭的抵抗表现为效应分子的产生增加和抑制受体如TIGIT和Pik3ip1的表达减少。删除Pik3ip1也能增强NK细胞抵抗黑色素瘤肺转移的能力。这些发现增强了他们对NK细胞衰竭的理解，并对预防以NK细胞为主题的癌症转移具有启示意义。

据了解，自然杀伤细胞（NK）在控制肿瘤转移中起着至关重要的作用，但当NK细胞进入衰竭状态时，其保护能力减弱。NK细胞衰竭的机制尚不完全清楚。

附：英文原文

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

Author: Zhang, Xiaolong, Yin, Zheng, Wu, Jie, Xiang, Xiao, Zou, Dawei, Wang, Guangchuan, Fu, Jinfei, Lan, Peixiang, Minze, Laurie J., Li, Xian C., Chen, Wenhao

Issue&Volume: 2025-06-16

Abstract: 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.

DOI: 10.1038/s41590-025-02176-w

Source: https://www.nature.com/articles/s41590-025-02176-w