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

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 () and Peng Xiao ()
Additional contact information
Zhenzhen Wen: Zhejiang University School of Medicine
Tong Liu: Cancer Hospital of Harbin Medical University
Xutao Xu: Zhejiang University School of Medicine
Nandini Acharya: The Ohio State University
Zhida Shen: Zhejiang University School of Medicine
Yunkun Lu: Zhejiang University School of Medicine
Junjie Xu: Zhejiang University School of Medicine
Ke Guo: Zhejiang University School of Medicine
Shuying Shen: Zhejiang University School of Medicine
Yuening Zhao: Zhejiang University School of Medicine
Pinli Wang: The Second Affiliated Hospital of Zhejiang University School of Medicine
Shumin Li: The Second Affiliated Hospital of Zhejiang University School of Medicine
Weiyu Chen: Zhejiang University School of Medicine
Hui Li: Zhejiang Cancer Hospital
Yimin Ding: Zhejiang University School of Medicine
Min Shang: Zhejiang University School of Medicine
Hongshan Guo: Zhejiang University
Yu Hou: Zhejiang University
Bijun Cui: Zhejiang University School of Medicine
Manlu Shen: Zhejiang University School of Medicine
Youling Huang: Zhejiang University School of Medicine
Ting Pan: Zhejiang University School of Medicine
Wang Qingqing: Zhejiang University School of Medicine
Qian Cao: Zhejiang University School of Medicine
Kai Wang: Zhejiang University School of Medicine
Peng Xiao: Zhejiang University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57603-1

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