Work

Spatial microbiome-metabolic crosstalk drives CD8+ T-cell exhaustion through the butyrate-HDAC axis in colorectal cancer

Year: 2025

Type: article

Abstract: 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 an 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.

Source: Frontiers in Microbiology

DOI: 10.3389/fmicb.2025.1704491