Tumor-resident probiotic Clostridium butyricum improves aPD-1 efficacy in colorectal cancer models by inhibiting IL-6-mediated immunosuppression

  • Cancer Cell. 2025 Jul 29:S1535-6108(25)00318-6. doi: 10.1016/j.ccell.2025.07.012.
Mingxu Xie  1 ,  Kai Yuan  1 ,  Yongxin Zhang  2 ,  Yating Zhang  1 ,  Ruyi Zhang  1 ,  Jiuhe Gao  1 ,  Wenchao Wei  1 ,  Lanping Jiang  1 ,  Tianhui Li  1 ,  Yanqiang Ding  1 ,  Luyao Wang  1 ,  Yufeng Lin  1 ,  Chi Chun Wong  1 ,  Jun Yu  3
Affiliations
  • 1. Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
  • 2. Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3. Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. Electronic address: [email protected].
PMID: 40780216 DOI: 10.1016/j.ccell.2025.07.012
Abstract

Most colorectal Cancer (CRC) patients do not respond to immune checkpoint blockade (ICB) therapy. Here, we identify Clostridium butyricum as a probiotic that boosts anti-PD-1 efficacy in CRC. In orthotopic allografts of microsatellite instability-high (MSI-H) and microsatellite stable (MSS) CRC, C. butyricum potentiates tumor suppressive effect of anti-PD-1, which is verified in AOM/DSS-induced CRC and germ-free mice. Single-cell RNA-seq reveals that C. butyricum activates cytotoxic CD8+ T lymphocytes (CTLs) and impairs tumor-associated macrophages (TAMs), especially in conjunction with anti-PD-1. Mechanistically, C. butyricum surface protein secD binds to CRC cell receptor glucose-regulated protein 78 (GRP78), which inactivates GRP78 and PI3K-AKT-NF-κB pathway, leading to reduced secretion of interleukin (IL)-6, an immunosuppressive cytokine that blunts CTLs and induces TAMs. Translational impact of C. butyricum in boosting anti-PD-1 efficacy is validated in huCD34+ humanized mice and autologous patient-derived CRC organoids-CTLs co-culture system. To summarize, C. butyricum is a promising Adjuvant to augment ICB therapy.

Keywords
Clostridium butyricum; colorectal cancer; cytotoxic CD8(+) T cells; immune checkpoint blockade; immunotherapy; intratumoral bacteria; patient-derived autologous organoids and TILs coculture; probiotics.
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