Lnk deficiency attenuates the immunosuppressive capacity of MDSCs via ferroptosis to suppress tumor development
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...
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07948-8 |
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| author | Jingwen Zhou Hui Yin JiaHua Pan Rui Yin Xin Wei Min Shen Liangliang Cai Ziqi Liu Jie Zhao Wenyan Chen Ruoxun Wang Xinrui Lan Wenshu Han Dongkun Li Xiaoyu Zhu Weijuan Gong Li Qian |
| author_facet | Jingwen Zhou Hui Yin JiaHua Pan Rui Yin Xin Wei Min Shen Liangliang Cai Ziqi Liu Jie Zhao Wenyan Chen Ruoxun Wang Xinrui Lan Wenshu Han Dongkun Li Xiaoyu Zhu Weijuan Gong Li Qian |
| author_sort | Jingwen Zhou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ac1aa19dbda240b8b2d413a95c2601b3 |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-ac1aa19dbda240b8b2d413a95c2601b32025-08-20T03:06:09ZengNature Publishing GroupCell Death and Disease2041-48892025-08-0116111610.1038/s41419-025-07948-8Lnk deficiency attenuates the immunosuppressive capacity of MDSCs via ferroptosis to suppress tumor developmentJingwen Zhou0Hui Yin1JiaHua Pan2Rui Yin3Xin Wei4Min Shen5Liangliang Cai6Ziqi Liu7Jie Zhao8Wenyan Chen9Ruoxun Wang10Xinrui Lan11Wenshu Han12Dongkun Li13Xiaoyu Zhu14Weijuan Gong15Li Qian16Key Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), School of Medicine, Yangzhou UniversityKey Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), School of Medicine, Yangzhou UniversityDepartment of Respiratory Medicine, Taizhou Second People’s Hospital Affiliated to Yangzhou University, Yangzhou UniversityKey Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), School of Medicine, Yangzhou UniversityKey Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), School of Medicine, Yangzhou UniversityKey Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), School of Medicine, Yangzhou UniversityKey Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), School of Medicine, Yangzhou UniversityKey Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), School of Medicine, Yangzhou UniversityKey Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), School of Medicine, Yangzhou UniversityKey Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), School of Medicine, Yangzhou UniversityKey Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), School of Medicine, Yangzhou UniversityKey Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), School of Medicine, Yangzhou UniversityKey Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), School of Medicine, Yangzhou UniversityKey Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), School of Medicine, Yangzhou UniversityDepartment of Ophthalmology, the Affiliated Hospital of Yangzhou UniversityKey Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), School of Medicine, Yangzhou UniversityKey Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), School of Medicine, Yangzhou UniversityAbstract 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.https://doi.org/10.1038/s41419-025-07948-8 |
| spellingShingle | Jingwen Zhou Hui Yin JiaHua Pan Rui Yin Xin Wei Min Shen Liangliang Cai Ziqi Liu Jie Zhao Wenyan Chen Ruoxun Wang Xinrui Lan Wenshu Han Dongkun Li Xiaoyu Zhu Weijuan Gong Li Qian Lnk deficiency attenuates the immunosuppressive capacity of MDSCs via ferroptosis to suppress tumor development Cell Death and Disease |
| title | Lnk deficiency attenuates the immunosuppressive capacity of MDSCs via ferroptosis to suppress tumor development |
| title_full | Lnk deficiency attenuates the immunosuppressive capacity of MDSCs via ferroptosis to suppress tumor development |
| title_fullStr | Lnk deficiency attenuates the immunosuppressive capacity of MDSCs via ferroptosis to suppress tumor development |
| title_full_unstemmed | Lnk deficiency attenuates the immunosuppressive capacity of MDSCs via ferroptosis to suppress tumor development |
| title_short | Lnk deficiency attenuates the immunosuppressive capacity of MDSCs via ferroptosis to suppress tumor development |
| title_sort | lnk deficiency attenuates the immunosuppressive capacity of mdscs via ferroptosis to suppress tumor development |
| url | https://doi.org/10.1038/s41419-025-07948-8 |
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