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<p>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 <i>Lnk</i><sup><i>–/–</i></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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月12日

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  • 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

摘要

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.