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
  • 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 [email protected] [email protected].
  • 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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