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<p>Overcoming immunosuppression in the tumor microenvironment (TME) is crucial for developing novel cancer immunotherapies. Here, we report that IL-16 administration enhances the polarization of T helper 1 (Th1) cells by inhibiting glutamine catabolism through the downregulation of glutaminase in CD4<sup>+</sup> T cells and increases the production of Th1 effector cytokine IFN-γ, thus improving anti-tumor immune responses. Moreover, we find that establishing an IL-16-dependent, Th1-dominant TME relies on mast cell-produced histamine and results in the increased expression of the CXCR3 ligands in tumor-associated macrophages (TAM), thereby improving the therapeutic effectiveness of immune checkpoint blockade (ICB). Cancer patients exhibit impaired production of IL-16, which correlates with poorer prognosis. Additionally, low IL-16 production is associated with unresponsiveness to immunotherapy in cancer patients. Collectively, our findings provided new insights into the biological function of IL-16, emphasizing its potential clinical significance as a therapeutic approach to augment anti-tumor immunity and sensitize ICB-based cancer immunotherapy.</p>

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Interleukin-16 enhances anti-tumor immune responses by establishing a Th1 cell-macrophage crosstalk through reprogramming glutamine metabolism in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月10日

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  • Zhenzhen Wen,
  • Tong Liu,
  • Xutao Xu,
  • Nandini Acharya,
  • Zhida Shen,
  • Yunkun Lu,
  • Junjie Xu,
  • Ke Guo,
  • Shuying Shen,
  • Yuening Zhao,
  • Pinli Wang,
  • Shumin Li,
  • Weiyu Chen,
  • Hui Li,
  • Yimin Ding,
  • Min Shang,
  • Hongshan Guo,
  • Yu Hou,
  • Bijun Cui,
  • Manlu Shen,
  • Youling Huang,
  • Ting Pan,
  • Wang Qingqing,
  • Qian Cao,
  • Kai Wang,
  • Peng Xiao

摘要

Overcoming immunosuppression in the tumor microenvironment (TME) is crucial for developing novel cancer immunotherapies. Here, we report that IL-16 administration enhances the polarization of T helper 1 (Th1) cells by inhibiting glutamine catabolism through the downregulation of glutaminase in CD4+ T cells and increases the production of Th1 effector cytokine IFN-γ, thus improving anti-tumor immune responses. Moreover, we find that establishing an IL-16-dependent, Th1-dominant TME relies on mast cell-produced histamine and results in the increased expression of the CXCR3 ligands in tumor-associated macrophages (TAM), thereby improving the therapeutic effectiveness of immune checkpoint blockade (ICB). Cancer patients exhibit impaired production of IL-16, which correlates with poorer prognosis. Additionally, low IL-16 production is associated with unresponsiveness to immunotherapy in cancer patients. Collectively, our findings provided new insights into the biological function of IL-16, emphasizing its potential clinical significance as a therapeutic approach to augment anti-tumor immunity and sensitize ICB-based cancer immunotherapy.