The dual role of Fusobacterium nucleatum in colorectal cancer: from oncogenic mechanisms to immunotherapy sensitization

Fusobacterium nucleatum ( Fn ) has emerged as a critical microbial modulator in the development, progression, and therapeutic response of colorectal cancer (CRC). High-resolution genomic evidence identifies Fn subsp. animalis Clade 2 ( Fna C2) as the predominant clade enriched in tumor microenvironments and invasive biofilms, favored by Fna C2-specific metabolic adaptations (utilizing ethanolamine and 1,2-propanediol) and a glutamate-dependent acid resistance (GDAR) system. At the molecular level, Fn drives oncogenesis, inflammation, and metastasis via the FadA/β-catenin and Fap2/TIGIT pathways, as well as the Toll-like receptor 4 (TLR4)/MyD88/NF-κB/microRNA-21 (miR-21) axis that suppresses RAS GTPase-activating protein 1 (RASA1) to hyperactivate RAS signaling. Fap2-mediated invasion further triggers interleukin-8 (IL-8) and C-X-C motif chemokine ligand 1 (CXCL1) secretion, recruiting myeloid-derived suppressor cells (MDSCs) and neutrophils to foster a pro-tumor niche. Additionally, Fn confers chemoresistance to 5-fluorouracil (5-FU) through BIRC3 (an inhibitor of apoptosis protein) upregulation and autophagy pathways. Paradoxically, Fn also acts as a “double-edged sword” by sensitizing microsatellite stable (MSS) CRC to immune checkpoint inhibitors (ICIs). This immunosensitization is mediated via a dual pathway: cyclic GMP-AMP synthase (cGAS)-STING activation enhancing tumor-infiltrating lymphocytes (TILs), and microbial butyrate acting as a histone deacetylase 3/8 (HDAC3/8) inhibitor to epigenetically reprogram CD8+ T cells against exhaustion. To address the spatial heterogeneity and the safety risks of live bacterial therapy, translational efforts are pivoting toward cell-free interventions such as postbiotics and STING agonists. This review comprehensively delineates the clade-specific traits of Fna C2 alongside broader Fn immunomodulatory mechanisms, highlighting its potential and current limitations as a diagnostic biomarker and therapeutic target in precision CRC care.