Lnk缺陷通过铁死亡减弱髓源性抑制细胞的免疫抑制能力以抑制肿瘤发展。

Lnk deficiency attenuates the immunosuppressive capacity of MDSCs via ferroptosis to suppress tumor development.

作者信息

Zhou Jingwen, Yin Hui, Pan JiaHua, Yin Rui, Wei Xin, Shen Min, Cai Liangliang, Liu Ziqi, Zhao Jie, Chen Wenyan, Wang Ruoxun, Lan Xinrui, Han Wenshu, Li Dongkun, Zhu Xiaoyu, Gong Weijuan, Qian Li

机构信息

Key Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), School of Medicine, Yangzhou University, Yangzhou, 225001, China.

Department of Clinical Laboratory Medicine, the Air Force Hospital of Eastern Theater Command, PLA, Nanjing, 210001, China.

出版信息

Cell Death Dis. 2025 Aug 12;16(1):610. doi: 10.1038/s41419-025-07948-8.

DOI:10.1038/s41419-025-07948-8

PMID:40796725

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12343911/

Abstract

A subset of immature myeloid cells known as myeloid-derived suppressor cells (MDSCs) play an immunosuppressive role and actively stimulate the growth of tumors. Lymphocyte adaptor protein (Lnk) regulates the development of hematopoietic stem cells and inflammatory CD8 T cells by inhibiting cytokine signaling. However, it is unclear how Lnk regulates the function of MDSCs during tumorigenesis. Here, using Lnk mice, we showed that Lnk deficiency inhibited tumor growth in an MDSC-dependent manner. Mechanistically, we demonstrated that Lnk deficiency weakened the immunosuppressive effects of MDSCs through ferroptosis. In addition, Lnk deficiency-induced ferroptosis was regulated by the Flt3/STAT1/IRF1/Alox12 axis. Besides, Lnk was more highly expressed in MDSCs from lung cancer patients. Knocking down Lnk in human MDSCs resulted in increased TNF-α and decreased Arg-1 expression. These findings demonstrate that the role of Lnk is vital in the immunosuppressive ability of MDSCs and offers a novel target for cancer treatment.

摘要

一种被称为髓源性抑制细胞（MDSCs）的未成熟髓样细胞亚群发挥免疫抑制作用，并积极刺激肿瘤生长。淋巴细胞衔接蛋白（Lnk）通过抑制细胞因子信号传导来调节造血干细胞和炎性CD8 T细胞的发育。然而，尚不清楚Lnk在肿瘤发生过程中如何调节MDSCs的功能。在此，我们使用Lnk基因敲除小鼠表明，Lnk缺陷以MDSC依赖的方式抑制肿瘤生长。从机制上来说，我们证明Lnk缺陷通过铁死亡削弱了MDSCs的免疫抑制作用。此外，Lnk缺陷诱导的铁死亡受Flt3/STAT1/IRF1/Alox12轴调控。此外，Lnk在肺癌患者的MDSCs中表达更高。在人MDSCs中敲低Lnk导致TNF-α增加和Arg-1表达降低。这些发现表明Lnk在MDSCs的免疫抑制能力中起着至关重要的作用，并为癌症治疗提供了一个新的靶点。