Fusobacterium nucleatum as a two-hit amplifier in colorectal cancer pathogenesis: intersection of local and systemic mechanisms via the gut–kidney axis

Colorectal cancer (CRC) is a complex malignancy driven by genetic, environmental, and lifestyle factors. A critical contributor to CRC tumor initiation and progression is gut microbial dysbiosis. Fusobacterium nucleatum, an oral commensal bacterium, is a potent promoter of malignancy rather than a passive colonizer. This review examines the molecular mechanisms by which F. nucleatum promotes CRC progression, focusing on one indirect systemic and three direct local mechanisms. First, the lipopolysaccharide–Toll-like receptor 4 axis sustains a chronic inflammatory loop that remodels the tumor microenvironment. Second, the fibroblast activation protein 2–T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain interaction facilitates immune evasion by suppressing T cell and natural killer cell cytotoxic activity. Third, the Fusobacterium adhesin A–E-cadherin/Wnt pathway acts as a potent “second hit,” amplifying β-catenin signaling and driving proliferation in cells with pre-existing mutations in adenomatous polyposis coli. Beyond these local effects, this review highlights a novel indirect mechanism involving the gut–kidney axis. Specifically, F. nucleatum is hypothesized to contribute to systemic levels of indoxyl sulfate, a uremic toxin that reinforces a systemic feedback loop via pro-proliferative signaling. These synergistic mechanisms collectively remodel the tumor microenvironment by promoting immune suppression, chronic inflammation, and metabolic reprogramming. Within this framework, F. nucleatum collaborates with genetic lesions to accelerate disease progression. This framework provides a crucial foundation for developing innovative diagnostics and microbe-targeted therapies—such as phage therapy and vaccines—to substantially improve the prognosis of patients with CRC.