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  3. Enhancing immunotherapy efficacy in NSCLC through the combined use of phenelzine and Akkermansia muciniphila to regulate gut microbial metabolite 5-HIAA

Enhancing immunotherapy efficacy in NSCLC through the combined use of phenelzine and Akkermansia muciniphila to regulate gut microbial metabolite 5-HIAA

  • J Immunother Cancer. 2025 Sep 10;13(9):e011831. doi: 10.1136/jitc-2025-011831.
Shilong Sun # 1 2,  Longhao Wang # 3,  Kang Cui # 4,  Yuchao Ding 1,  Yujie Wei 1,  Yuanyuan Zheng 1 5,  Zhibo Shen 5,  Lili Zhu 1,  Yaqi Yang 1,  Pu Yu 4,  Yiqiong Song 1,  Ke Chao 1,  Yixing Zhang 1,  Yahao Ge 1,  Wenxuan Ji 1,  Chunwei Li 1,  Gautam Sethi 6,  Lifeng Li 7 8 9,  Jie Zhao 7 2
Affiliations

Affiliations

  • 1 National Engineering Laboratory for Internet Medical Systems and Applications, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 2 Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 3 Department of Oncology, Henan Provincial People's Hospital, Zhengzhou, Henan, China.
  • 4 Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 5 Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 6 Department of Pharmacology, National University of Singapore, Singapore.
  • 7 National Engineering Laboratory for Internet Medical Systems and Applications, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China zhaojie@zzu.edu.cn lilifeng0317@163.com.
  • 8 Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 9 Hospital of Traditional Chinese Medicine of Xinjiang Uygur Autonomous Region, Uygur Autonomous Region, Xinjiang, China.
  • # Contributed equally.
PMID: 40930748 DOI: 10.1136/jitc-2025-011831
Abstract

Background: Improving the efficacy of anti-programmed death 1 (PD-1) monoclonal antibody (mAb) therapy remains a major challenge for Cancer Immunotherapy in non-small cell lung Cancer (NSCLC). Gut microbial metabolites can influence immunotherapy efficacy.

Methods: ELISA was used to compare the serum 5-hydroxyindoleacetic acid (5-HIAA) level in patients with NSCLC. Humanized mice were constructed to observe the effect of 5-HIAA on immunotherapy. RNA-seq and flow cytometry were used to analyze the effect of 5-HIAA on tumor-infiltrating lymphocytes. The effects of phenelzine (Phe) and Akkermansia muciniphila (AKK) on 5-HIAA synthesis, antitumor immunity and immunotherapy efficacy were analyzed. Finally, the synergistic effect of Phe combined with AKK on anti-PD-1 mAb was observed.

Results: Here we found that 5-HIAA, which is regulated by gut microbiota, has increased concentrations in the serum of non-responders to immunotherapy. Supplementation of 5-HIAA inhibited the efficacy of anti-PD-1 mAb and tumor infiltration of CD8+ T cells. The use of Monoamine Oxidase Inhibitor (MAO-I) Phe inhibited the synthesis of 5-HIAA, then improved the efficacy of anti-PD-1 mAb. In addition, supplementation of AKK can also decrease 5-HIAA in serum. Finally, the combination of Phe and AKK maximally inhibited 5-HIAA synthesis and improved immunotherapy efficacy.

Conclusions: Our investigations reveal that alterations in gut microbial composition leading to increased 5-HIAA synthesis can negatively impact CD8+ T cell functionality and the success of immunotherapy. The combination of Phe and AKK supplementation holds potential for optimizing immunotherapy efficacy.

Keywords

Immunotherapy; Lung Cancer.

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