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

作者：Shilong Sun, Longhao Wang, Kang Cui, Yuchao Ding, Yujie Wei, Yuanyuan Zheng, Zhibo Shen, Lili Zhu, Yaqi Yang, Yu Pu, Yiqiong Song, Ke Chao, Yixing Zhang, Yahao Ge, Wenxuan Ji, Chun‐Wei Li, Gautam Sethi, Lifeng Li, Jie Zhao · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2025-011831 · 被引用次数：4 · 研究领域：Gut microbiota and health、Cancer Immunotherapy and Biomarkers、Immune Cell Function and Interaction

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...