2. Academic Validation
  3. Fusobacterium nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer

Fusobacterium nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer

  • Cell Host Microbe. 2023 May 10;31(5):781-797.e9. doi: 10.1016/j.chom.2023.04.010.
Shan-Shan Jiang 1,  Yi-Le Xie 1,  Xiu-Ying Xiao 2,  Zi-Ran Kang 1,  Xiao-Lin Lin 2,  Lu Zhang 1,  Chu-Shu Li 1,  Yun Qian 1,  Ping-Ping Xu 1,  Xiao-Xu Leng 1,  Li-Wei Wang 2,  Shui-Ping Tu 2,  Ming Zhong 3,  Gang Zhao 3,  Jin-Xian Chen 3,  Zheng Wang 3,  Qiang Liu 4,  Jie Hong 1,  Hao-Yan Chen 1,  Ying-Xuan Chen 5,  Jing-Yuan Fang 6
Affiliations

Affiliations

  • 1 Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China.
  • 2 Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
  • 3 Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
  • 4 Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
  • 5 Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China. Electronic address: yingxuanchen71@sjtu.edu.cn.
  • 6 Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China. Electronic address: jingyuanfang@sjtu.edu.cn.
PMID: 37130518 DOI: 10.1016/j.chom.2023.04.010
Abstract

Immune Checkpoint blockade therapy with anti-PD-1 monoclonal antibody (mAb) is a treatment for colorectal Cancer (CRC). However, some patients remain unresponsive to PD-1 blockade. The gut microbiota has been linked to immunotherapy resistance through unclear mechanisms. We found that patients with metastatic CRC who fail to respond to immunotherapy had a greater abundance of Fusobacterium nucleatum and increased succinic acid. Fecal microbiota transfer from responders with low F. nucleatum, but not F. nucleatum-high non-responders, conferred sensitivity to anti-PD-1 mAb in mice. Mechanistically, F. nucleatum-derived succinic acid suppressed the cGAS-interferon-β pathway, consequently dampening the antitumor response by limiting CD8+ T cell trafficking to the tumor microenvironment (TME) in vivo. Treatment with the Antibiotic metronidazole reduced intestinal F. nucleatum abundance, thereby decreasing serum succinic acid levels and resensitizing tumors to immunotherapy in vivo. These findings indicate that F. nucleatum and succinic acid induce tumor resistance to immunotherapy, offering insights into microbiota-metabolite-immune crosstalk in CRC.

Keywords

Fusobacterium nucleatum; cGAS-IFN-β pathway; colorectal cancer; immunotherapy; succinic acid.

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