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Metformin facilitates anti-PD-L1 efficacy through the regulation of intestinal microbiota

Genes & Immunity volume 25, pages 7–13 (2024)Cite this article

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Abstract

Metformin is a synthetic biguanide proven to have beneficial effects against various human diseases. Research has confirmed that metformin exerts its effects by regulating the composition of intestinal microbiota. The composition of intestinal microbiota influences the efficacy of anti-PD-L1 immunotherapy. We assume that the regulation of metformin on intestinal microbiota could enhance the therapeutic efficiency of anti-PD-L1 antibodies. In Lewis lung cancer-bearing C57BL/6J mice, we find that metformin enhances PD-L1 antibody efficacy mainly depending on the existence of gut microbiota, and metformin increases the anti-tumor immunity through modulation of intestinal microbiota and affects the integrity of the intestinal mucosa. Antibiotic depletion of gut microbiota abolished the combination efficacy of PD-L1 antibody and metformin, implying the significance of intestinal microbiota in metformin’s antitumor action. Combining anti-PD-L1 antibody with metformin provoked tumor necrosis by causing increased CD8 T-cell infiltration and IFN-γ expression. In conclusion, metformin could be employed as a microecological controller to prompt antitumor immunity and increase the efficacy of anti-PD-L1 antibodies. Our study provided reliable evidence that metformin could be synergistically used with anti-PD-L1 antibody to enhance the anti-cancer effect.

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Fig. 1: In vivo anti-tumor effect of metformin (Met) was related to enhance immunology.
Fig. 2: metformin causes intestinal microbiota alteration in tumor-bearing mice.
Fig. 3: B. bifidum and A. muciniphila exerted anti-tumor activity by modulating intestinal microbiota.
Fig. 4: metformin might improve the efficacy of anti-PD-L1 by increasing immunization.
Fig. 5: Metformin enhanced the efficacy of anti-PD-L1 antibody dependent with the existence of gut microbiota.

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Data are available from the authors upon reasonable request.

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Acknowledgements

The current study was supported by the Medical Science and Technology Project of Hebei Provincial Health Commission (numbers 20230101 and 20211364).

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Author notes

  1. These authors contributed equally: Xiaopeng Zhao, Chuang Liu.

Authors and Affiliations

  1. Department of Thoracic Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang City, 050011, China

    Xiaopeng Zhao, Licheng Peng & Hongyan Wang

  2. Department of Thoracic Surgery, the Fourth Central Hospital of Baoding City, Baoding, China

    Chuang Liu

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  1. Xiaopeng Zhao
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  4. Hongyan Wang
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Contributions

XPZ and HYW are responsible for conception and study of the study; XPZ and CL are responsible for the conduction the experiments; LCP and XPZ are responsible for data acquisition and statistical analysis. The manuscript was written by XPZ and supervised by HYW.

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Correspondence to Hongyan Wang.

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Zhao, X., Liu, C., Peng, L. et al. Metformin facilitates anti-PD-L1 efficacy through the regulation of intestinal microbiota. Genes Immun 25, 7–13 (2024). https://doi.org/10.1038/s41435-023-00234-7

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