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

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

  • Nat Commun. 2025 Mar 10;16(1):2362. doi: 10.1038/s41467-025-57603-1.
Zhenzhen Wen # 1,  Tong Liu # 2,  Xutao Xu # 1,  Nandini Acharya 3,  Zhida Shen 4,  Yunkun Lu 5,  Junjie Xu 5,  Ke Guo 1,  Shuying Shen 6,  Yuening Zhao 1,  Pinli Wang 7,  Shumin Li 7,  Weiyu Chen 8,  Hui Li 9,  Yimin Ding 1,  Min Shang 4,  Hongshan Guo 10,  Yu Hou 10,  Bijun Cui 11,  Manlu Shen 1,  Youling Huang 1,  Ting Pan 12 13,  Wang Qingqing 14 15,  Qian Cao 16,  Kai Wang 17,  Peng Xiao 18 19 20
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Department of Breast Surgery, Cancer Hospital of Harbin Medical University, Harbin, China.
  • 3 Pelotonia Institute for Immuno-Oncology, OSUCCC-James, The Ohio State University, Columbus, OH, USA.
  • 4 Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 5 Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 6 Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
  • 8 Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China.
  • 9 Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China.
  • 10 Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
  • 11 Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 12 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
  • 13 The Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, China.
  • 14 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China. wqq@zju.edu.cn.
  • 15 The Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, China. wqq@zju.edu.cn.
  • 16 Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. caoq@zju.edu.cn.
  • 17 Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China. kaiw@zju.edu.cn.
  • 18 Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. tulipxp@zju.edu.cn.
  • 19 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China. tulipxp@zju.edu.cn.
  • 20 The Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, China. tulipxp@zju.edu.cn.
  • # Contributed equally.
PMID: 40064918 DOI: 10.1038/s41467-025-57603-1
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.

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