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 |
| Published: |
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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| Summary: | 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. |
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| ISSN: | 2041-4889 |