Unveiling Fusobacterium nucleatum’s role in colorectal cancer: the inflammatory microenvironment connection

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Background Fusobacterium nucleatum (Fn), a gram-negative oral bacterium, has been implicated in promoting colorectal cancer (CRC) progression by modulating the inflammatory microenvironment. Recent studies have shown that gut microbiota imbalance plays a crucial role in CRC development, and Fn, specifically, has been found to exist in the intestine and exert pro-tumorigenic effects. However, the precise mechanisms underlying Fn-induced CRC progression remain elusive. Methods A systematic experimental strategy was adopted to explore the function of Fusobacterium nucleatum (Fn) in colorectal cancer (CRC) progression. Tissue specimens were collected from healthy volunteers, patients with ulcerative colitis (UC), colorectal adenoma (CRA) and CRC at the First Affiliated Hospital of Henan University of Science and Technology via colonoscopy and surgical resection. Two CRC mouse models, subcutaneous MC38 model and AOM-DSS orthotopic model, were constructed, followed by intratumoral injection or oral gavage of Fn, Streptococcus mutans (S.M.) or normal saline. qPCR was used to quantify Fn abundance in colorectal tissues. IHC and FISH detected inflammatory cytokines and immune cells in tumor tissues. 16S rRNA amplicon sequencing analyzed Fn-mediated alterations in mouse gut microbiota. Flow cytometry and ELISA evaluated immune cell subsets and inflammatory cytokine levels. Western blot examined NLRP3 inflammasome and other proteins expression. Results In this study, we employed two mouse models of CRC (MC38 subcutaneous and AOM-DSS orthotopic models) to investigate the role of Fn in CRC progression. Our findings demonstrated that Fn administration significantly increased tumor growth compared to controls. Quantitative PCR confirmed elevated Fn abundance in CRC tissues, and microbiome analysis revealed distinct bacterial clades in Fn-treated mice. Immunofluorescence analysis showed enrichment of myeloid cells (CD45/CD11b, CD11C, F4/80,MHCI,MHCII) in tumors, suggesting that Fn reshapes the immune landscape towards a proinflammatory state. In vitro and in vivo experiments further revealed that Fn selectively expands myeloid-derived immune cells. Critically, Fn failed to induce tumor growth in NLRP3 -/- mice, confirming that NLRP3 inflammasome activation is a key mechanism in Fn-induced CRC progression. Conclusion Our results establish Fn as a driver of CRC progression through bone marrow-derived immune cell recruitment and NLRP3-dependent inflammatory microenvironment induction. These findings provide new insights into the mechanisms by which Fn contributes to CRC development and suggest potential therapeutic targets for CRC prevention and treatment.

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