Interleukin-16 enhances anti-tumor immune responses by establishing a Th1 cell-macrophage crosstalk through reprogramming glutamine metabolism in mice PMID: 40064918

ADC Targets in Oncology

2026-04-10

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.

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.