Lnk deficiency attenuates the immunosuppressive capacity of MDSCs via ferroptosis to suppress tumor development
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<sup>+</sup> T cells by inhibiting cytokine signaling. However, it is unclear how Lnk regulates the function of MDSCs during tumorigenesis. Here, using Lnk<sup>-/-</sup> 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.
Authors
- Weijuan Gong (ORCID: https://orcid.org/0000-0002-8543-1314)
- Xin Wei (ORCID: https://orcid.org/0000-0001-5446-2372)
- Jingwen Zhou (ORCID: https://orcid.org/0000-0002-3949-3733)
- Wenshu Han
- Ziqi Liu (ORCID: https://orcid.org/0000-0002-0977-2141)
- Ruoxun Wang (ORCID: https://orcid.org/0000-0002-8147-3779)
- Wenyan Chen (ORCID: https://orcid.org/0000-0001-6872-7378)
- Liangliang Cai (ORCID: https://orcid.org/0009-0008-4963-4430)
- Xiaoyu Zhu (ORCID: https://orcid.org/0000-0003-4846-6398)
- Jennifer Pan (ORCID: https://orcid.org/0000-0001-6713-6402)
- Min Shen (ORCID: https://orcid.org/0000-0003-1912-126X)
- Dawei Li (ORCID: https://orcid.org/0000-0002-2283-7763)
- Rui Yin (ORCID: https://orcid.org/0000-0001-5935-3706)
- Hui Yin (ORCID: https://orcid.org/0000-0001-8040-8812)
- Jie Zhao (ORCID: https://orcid.org/0009-0006-7598-4085)
- Li Qian
- Xinrui Lan
Institutions
- 81th Hospital of PLA (CN)
- Northern Jiangsu People's Hospital (CN)
- Yangzhou University (CN)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1038/s41419-025-07948-8
- Citations
- 2
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.59
Funders
- National Natural Science Foundation of China
- Government of Jiangsu Province
- Yangzhou University