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
  • 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. [email protected].
  • 15. The Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, China. [email protected].
  • 16. Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 17. Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China. [email protected].
  • 18. Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 19. Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 20. The Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, China. [email protected].
  • # 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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