ORIGINAL RESEARCH article
Front. Microbiol.
Sec. Systems Microbiology
This article is part of the Research TopicUnlocking the Potential of the Microbiome in Cancer TherapyView all 13 articles
Spatial microbiome-metabolic crosstalk drives CD8+ T-cell exhaustion through butyrate-HDAC axis in colorectal cancer
Provisionally accepted
- 1Department of Oncology, First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
- 2Department of Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
- 3Department of Anesthesiology, Medical College of Jinzhou Medical University, Jinzhou, China
- 4Huashan School of Medicine,Shanghai Medical College, Fudan University, Shanghai, China
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Background: The spatial organization of intratumoral microbiota and its metabolic impact on immunotherapy response in colorectal cancer (CRC) is unclear, limiting targeted interventions. Methods: We integrated single-cell RNA-seq, spatial transcriptomics, and microbial multi-omics from a discovery cohort of 23 treatment-naïve CRC patients. Findings were validated in an independent validation cohort from The Cancer Genome Atlas (TCGA-CRC, n=159). Results: Spatial depletion of Streptococcus and Acetivibrio in tumor niches disrupts butyrate-histone deacetylase (HDAC) signaling, leading to programmed cell death 1(PDCD1) hyperacetylation and CD8+T-cell exhaustion. The Colorectal Cancer Microbiome Score (CMS) may serve as a predictive biomarker for immunotherapy response and HDAC inhibitor-based combination therapy. We developed the CMS, a spatial biomarker that stratifies patients by microbial-metabolic dysfunction, predicting immunotherapy resistance (e.g., higher tumor immune dysfunction and exclusion (TIDE) scores; p < 0.01) and guiding combinatorial HDAC inhibition for CMS-defined subgroups. In silico fecal microbiota transplantation (FMT) validated CMS as a actionable target for microbiota modulation. Butyrate supplementation in vitro restored HDAC activity and reduced PD-1 expression on CD8+T cells, validating the proposed mechanism. Conclusion: Our study unveils a spatially-defined, microbiome-driven metabolic niche that epigenetically programs CD8+T-cell exhaustion via the butyrate-HDAC axis, revealing a targetable mechanism to overcome immunotherapy resistance in CRC.
Keywords: Spatial microbiome, Butyrate metabolism, CD8+ T-cell exhaustion, HDAC inhibition, Microbiome-metabolic-immune crosstalk, colorectal cancer
Received: 13 Sep 2025; Accepted: 14 Nov 2025.
Copyright: © 2025 Chen, Zhang, Zhang, Wang, Dou, Wang, Huang and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Xiaomei Liu, 13644163026@163.com
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