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<p>Myeloid-derived suppressor cells (MDSCs) play a crucial role in tumor-associated immune suppression and in impeding immune checkpoint blockade (ICB) therapies; however, effective intervention strategies targeting MDSCs remain limited. In this study, we observed a positive correlation between spleen tyrosine kinase (SYK) activity in immune cells and tumor progression in human cancers. Utilizing a mouse model with a gain-of-function SYK<sup>S544Y</sup> mutation, we demonstrated that SYK activation promotes tumorigenesis in carcinogen-induced and xenograft models across multiple cancer types, largely through MDSC-dependent mechanisms. Mechanistically, SYK activates the JAK-STAT-CXCR2 signaling axis, enhancing MDSC migration and suppressing antitumor T cell responses. Notably, pharmacological inhibition of SYK not only inhibited tumor growth but also enhanced the therapeutic effect of anti-PD-1 in mouse models and patient-derived tumor organoid models. Our findings highlight the immunoregulatory role of SYK in tumor progression and suggest that targeting SYK represents a promising strategy to remodel the tumor microenvironment and enhance the efficacy of checkpoint blockade immunotherapy.</p>

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Targeting SYK to alleviate MDSC-driven immunosuppression and augment anti-PD1 efficacy

  • 期刊论文

  • 发表日期：

    2026年6月30日

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  • Zhiyang Zeng,
  • Xiya Cao,
  • Changwei Li,
  • Youyuan He,
  • Haozhe Guo,
  • Xiaoya Cao,
  • Tingyue Gong,
  • Jialiang Sun,
  • Yaqiang Hu,
  • Zhongwei Hu,
  • Yuxuan Lai,
  • Dan Zhang,
  • Neil Warner,
  • Holm H. Uhlig,
  • Qi Li,
  • Aleixo M. Muise,
  • Yamin Tan,
  • Ying Huang,
  • Lianfu Deng,
  • Liufu Deng,
  • Zhenliang Sun,
  • Ming Zhong,
  • Xueli Zhang,
  • Dali Li

摘要

Myeloid-derived suppressor cells (MDSCs) play a crucial role in tumor-associated immune suppression and in impeding immune checkpoint blockade (ICB) therapies; however, effective intervention strategies targeting MDSCs remain limited. In this study, we observed a positive correlation between spleen tyrosine kinase (SYK) activity in immune cells and tumor progression in human cancers. Utilizing a mouse model with a gain-of-function SYKS544Y mutation, we demonstrated that SYK activation promotes tumorigenesis in carcinogen-induced and xenograft models across multiple cancer types, largely through MDSC-dependent mechanisms. Mechanistically, SYK activates the JAK-STAT-CXCR2 signaling axis, enhancing MDSC migration and suppressing antitumor T cell responses. Notably, pharmacological inhibition of SYK not only inhibited tumor growth but also enhanced the therapeutic effect of anti-PD-1 in mouse models and patient-derived tumor organoid models. Our findings highlight the immunoregulatory role of SYK in tumor progression and suggest that targeting SYK represents a promising strategy to remodel the tumor microenvironment and enhance the efficacy of checkpoint blockade immunotherapy.