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  • Fusobacterium nucleatum in Colorectal Cancer: Molecular Crosstalk Between Microbial Virulence and Host Oncogenic Signaling

  • Delara Mansouri,1 Aida Alipashazadeh,2,*
    1. Department of Biology, Bab.C., Islamic Azad University, Babol/Iran
    2. Department of Microbiology, Faculty of Biological Sciences, NT.C., Islamic Azad University, Tehran, Iran


  • Introduction: According to the World Health Organization (WHO), updated on 13 February 2026, colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related deaths worldwide. Its development is influenced by genetic, epigenetic, and environmental factors, particularly the gut microbiota. A healthy microbiota supports host health, but disruptions, termed dysbiosis, can foster a pathogenic environment conducive to tumorigenesis. Notably, the bacterium Fusobacterium nucleatum (Fn) is linked to CRC and exhibits increased virulence in specific clades, particularly Fna C2, which colonizes CRC tissues extensively. In terms of mechanism, Fn promotes tumour growth through two main pathways: FadA activates the Wnt/β-catenin pathway by binding to E-cadherin; meanwhile, LPS derived from Fn triggers the TLR4/MyD88/NF-κB pathway, leading to an increase in miR-21, inhibition of RASA1, and activation of RAS/MAPK. Research gaps remain, pressing the need for studies utilizing primary cancer cells and a heightened focus on strain interactions within the microbiota. This review evaluates the molecular interactions involving F. nucleatum in CRC, emphasizing the significance of strain-level and polymicrobial dynamics in oncogenic signaling.
  • Methods: The relevant literature for this review was identified from PubMed and Google Scholar databases in the period of [2017] to [2026] using search terms related to [Fusobacterium nucleatum, FadA, Fap2, LPS], [16S rRNA sequencing, FISH, IHC, cell culture animal models, and signaling pathways. Across the reviewed studies, the most common methods for Fn profiling were 16S rRNA sequencing, qPCR, and FISH, frequently combined with cell culture and animal models such as AOM/DSS and Villin-Cre/KrasG12D mice. Western blot, immunohistochemistry, and immunoprecipitation were widely used to mechanistically analyze Fn–host interactions and the downstream signaling.
  • Results: Across the reviewed literature, Fusobacterium nucleatum (Fn) is consistently linked to the development of colorectal cancer (CRC), immune modulation, metastasis, and chemoresistance. Mechanistically, two primary pathways are frequently reported. In colorectal cancer cell lines and in mouse models, the FadA adhesin binds to E-cadherin, causing β-catenin to be released into the cytoplasm; β-catenin then gets into the nucleus where it activates MYC and cyclin D1, thereby increasing cell proliferation. Moreover, both in vitro and in vivo studies have shown that Fn lipopolysaccharide activates TLR4, which in turn recruits MyD88 and activates NF-κB. NF-κB in this case increases miR-21; miR-21 then inhibits RASA1, a negative regulator of RAS, so that RAS/MAPK signalling becomes active and promotes proliferation. Furthermore, NF-κB causes the production of IL-6, IL-8, and TNF-α, leading to a pro-inflammatory microenvironment. In colorectal cancer cell lines and mouse models carrying the KRAS p.G12D mutation, Fn binds to DHX15, enhancing ERK/STAT3 signalling and speeding up tumor growth. Fn also affects autophagy, which contributes to chemoresistance. From an immunological point of view, in vitro studies show that Fap2 binds to TIGIT on T and NK cells, thereby blocking their cytotoxic activity, while CbpF binds to CEACAM1 and suppresses T cell function. In mouse models, Fn recruits MDSCs that deplete amino acids and express PD-L1, thus reducing T cell activation. Further in vitro studies indicate that Fn increases the expression of PD-L1 and CD47 through MYC, which helps in immune evasion. Both in vivo and human studies associate Fn with EMT, MMP-9, and metastasis. However, these effects are context-dependent and vary according to the Fn clade, the type of tumor, the co-microbiota, and the model used. Overall, there is a gap between the findings of academic research and human practice that needs further investigation and clinical studies.
  • Conclusion: Overall, the evidence suggests that Fn is an important microbial component in colorectal cancer and that its effects go well beyond carcinogenesis to involve immune system regulation, metastasis, and response to treatment. Interestingly, what is important regarding the influence of Fn on the progress of colorectal cancer is that this occurs via a number of pathways in the host rather than through a single pathway. However, it should be mentioned that the effect of Fn on CRC is not the same all the time and depends on many factors, such as the strain/clade of Fn itself, the tumor type, microbiome, and so on. There are, nevertheless, important limitations in the current evidence, including the predominant reliance on CRC cell-line models, limited consideration of intraspecies heterogeneity, and incomplete understanding of Fn interactions with other microorganisms within the tumor microenvironment.
  • Keywords: Colorectal Cancer; Fusobacterium nucleatum; Oncogenic signaling; Strain-level heterogeneity

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