Figure 3. Potential mechanisms of Fusobacterium nucleatum activity in CRC.

(A) Fusobacterium adhesin A (FadA) binding to E-cadherin increases β-catenin and WNT signaling and upregulates annexin A1 that drives epithelial cell proliferation. FadA also has amyloid-like properties that enhance F. nucleatum (Fn) adhesion to cancer cells. (B) Fusobacterium autotransporter protein 2 (Fap2) binds d-galactose-β(1-3)-N-acetyl-d-galactosamine (Gal-GalNAc) on cancer cells and recruits Fn to tumors. Fap2 also binds to T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) and impairs T and NK cell function, reduces cytotoxicity, and promotes immune cell death, resulting in tumor escape from immunosurveillance. Fap2⁺ Fn activates epithelial and myeloid cells and induces a pro-tumorigenic inflammatory response. (C) Fn LPS induces the expression of microRNA-21 in colon epithelial cells in a TLR4-dependent manner, which results in dysregulated cell proliferation and tumor growth. This same pathway also increases cancer cell autophagy, which enhances resistance to chemotherapy-induced cell death.