Targeting spermine metabolism to overcome immunotherapy resistance in pancreatic cancer

Hanshen Yang, Xiaozhen Zhang, Sirui Zhang, Yanqing Yang, Yan Chen, Yangwei Jiang, Qingsong Lu, Lingyue Liu, Mengyi Lao, Weiran Du, Kang Sun, Lihong He, Jiatao Shi, Xinyuan Liu, Jinyuan Song, Na Lu, Junming Huang, Jinyan Huang, Ruhong Zhou, Xiongbin Lu (), Tingbo Liang () and Xueli Bai ()
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Hanshen Yang: Zhejiang University
Xiaozhen Zhang: Zhejiang University
Sirui Zhang: Zhejiang University
Yanqing Yang: Zhejiang University
Yan Chen: Zhejiang University
Yangwei Jiang: Zhejiang University
Qingsong Lu: Zhejiang University
Lingyue Liu: Zhejiang University
Mengyi Lao: Zhejiang University
Weiran Du: Zhejiang University
Kang Sun: Zhejiang University
Lihong He: Zhejiang University
Jiatao Shi: Zhejiang University
Xinyuan Liu: Zhejiang University
Jinyuan Song: Zhejiang University
Na Lu: Zhejiang University
Junming Huang: Zhejiang University
Jinyan Huang: Zhejiang University
Ruhong Zhou: Zhejiang University
Xiongbin Lu: Zhejiang University
Tingbo Liang: Zhejiang University
Xueli Bai: Zhejiang University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract While dysregulation of polyamine metabolism is frequently observed in cancer, it is unknown how polyamines alter the tumor microenvironment (TME) and contribute to therapeutic resistance. Analysis of polyamines in the plasma of pancreatic cancer patients reveals that spermine levels are significantly elevated and correlate with poor prognosis. Using a multi-omics approach, we identify Serpinb9 as a vulnerability in spermine metabolism in pancreatic cancer. Serpinb9, a serine protease inhibitor, directly interacts with spermine synthase (SMS), impeding its lysosome-mediated degradation and thereby augmenting spermine production and secretion. Mechanistically, the accumulation of spermine in the TME alters the metabolic landscape of immune cells, promoting CD8+ T cell dysfunction and pro-tumor polarization of macrophages, thus creating an immunosuppressive microenvironment. Small peptides that disrupt the Serpinb9-SMS interaction significantly enhance the efficacy of immune checkpoint blockade therapy. Together, our findings suggest that targeting spermine metabolism is a promising strategy to improve pancreatic cancer immunotherapy.

Date: 2025
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DOI: 10.1038/s41467-025-63146-2

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