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Background <p>Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. While immunotherapy is effective in microsatellite instability-high (MSI-H) CRC, its benefits in microsatellite-stable (MSS) CRC are limited. Radiotherapy may modify the immune microenvironment in MSS-CRC, enhancing immunotherapy efficacy, but individual responses vary.</p> Methods <p>We employed MSS-CRC mouse models to examine the effects of combined radiotherapy and immunotherapy, with and without antibiotics (ABX). Various analyses, including metagenomic, nontargeted metabolomic, and gas chromatography-mass spectrometry (GC-MS), were performed to identify factors influencing treatment outcomes. Flow cytometry, immunohistochemistry and in vivo antibody blockade experiments assessed the role of metabolites and bacteria on CD8<sup>+</sup> T cell infiltration and treatment responses, complemented by transcriptomic sequencing and molecular biology experiments.</p> Results <p>Our analyses identified propionic acid and <i>Bacteroides fragilis</i> (<i>B. fragilis</i>) as crucial factors enhancing the efficacy of combined therapies in MSS-CRC. Both propionic acid and <i>B. fragilis</i> improved CD8<sup>+</sup> T cell infiltration and treatment outcomes, with molecular assays indicating that propionic acid facilitates H3K14 acetylation, activating the Meox1-Cxcr6/Ccl5 axis.</p> Conclusions <p>This study highlights the pivotal role of the gut microbiome, specifically propionic acid and <i>B. fragilis</i>, in modulating the efficacy of combined radiotherapy and immunotherapy in MSS-CRC.</p> <p></p>

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Impact of gut microbiome on radiotherapy and immunotherapy efficacy in microsatellite-stable colorectal cancer: role of propionic acid and B. fragilis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月26日

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  • Lu Yu,
  • Qiqing Guo,
  • Xinyi Gu,
  • Zihuan Wang,
  • Jiaying Li,
  • Xusheng Wang,
  • Zi Xu,
  • Yafang Wang,
  • Yuqin Zhang,
  • Yaowei Zhang,
  • Yanqing Ding,
  • Zhenhui Chen,
  • Keli Chen,
  • Yi Ding

摘要

Background

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. While immunotherapy is effective in microsatellite instability-high (MSI-H) CRC, its benefits in microsatellite-stable (MSS) CRC are limited. Radiotherapy may modify the immune microenvironment in MSS-CRC, enhancing immunotherapy efficacy, but individual responses vary.

Methods

We employed MSS-CRC mouse models to examine the effects of combined radiotherapy and immunotherapy, with and without antibiotics (ABX). Various analyses, including metagenomic, nontargeted metabolomic, and gas chromatography-mass spectrometry (GC-MS), were performed to identify factors influencing treatment outcomes. Flow cytometry, immunohistochemistry and in vivo antibody blockade experiments assessed the role of metabolites and bacteria on CD8+ T cell infiltration and treatment responses, complemented by transcriptomic sequencing and molecular biology experiments.

Results

Our analyses identified propionic acid and Bacteroides fragilis (B. fragilis) as crucial factors enhancing the efficacy of combined therapies in MSS-CRC. Both propionic acid and B. fragilis improved CD8+ T cell infiltration and treatment outcomes, with molecular assays indicating that propionic acid facilitates H3K14 acetylation, activating the Meox1-Cxcr6/Ccl5 axis.

Conclusions

This study highlights the pivotal role of the gut microbiome, specifically propionic acid and B. fragilis, in modulating the efficacy of combined radiotherapy and immunotherapy in MSS-CRC.