Abstract
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Background: Interactions among intratumoral microbiota, immune cells, tumor and stromal components are critical to the progression of colorectal cancer (CRC), yet the mechanisms remain incompletely defined.
Objective: This study aimed to investigate how multiple intratumoral microbiota species contribute to CRC pathogenesis through cellular interactions.
Design: We employed multi-omics analysis of clinical CRC samples to determine the correlations among transcriptional profiles, gut microbiota composition, and immune cell infiltration. Findings were functionally validated using in vitro assays and an AOM-DSS CRC mouse model. The impact of gut microbiota on tumor-infiltrating lymphocytes in AOM-DSS mouse model was further interrogated using single-cell RNA sequencing analysis.
Results: We identified Bacteroides fragilis (B.fragilis) and Fusobacterium nucleatum (F.nucleatum) were identified as the most enriched bacteria in CRC tumors, with their co-colonization correlating with IL-17 pathway activation and regulatory T cell (Treg) accumulation. Mechanistically, these bacteria synergistically activated cancer-associated fibroblast (CAF) via the NF-κB pathway. Activated CAFs secreted IL-6, GM-CSF, and G-CSF, driving myeloid-derived suppressor cell (MDSC) expansion and subsequent Treg differentiation — establishing a microbiota–CAF–MDSC–Treg axis. In vivo, dual bacterial colonization increased tumor burden and Treg/MDSC infiltration, which was abrogated upon CD4⁺ T cell depletion. Single-cell analysis confirmed Treg enrichment and upregulation of NF-κB/IL-17 pathway genes in CAFs and MDSCs from co-colonized mice.
Conclusion: Our study reveals a cooperative mechanism by which intratumoral bacteria remodel the CRC immune microenvironment through stromal cell reprogramming. The identified Microbiota–CAF–MDSC–Treg axis represents a potential therapeutic target for modulating immunosuppression in CRC.
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