The Dual Face of Fusobacterium nucleatum in Cancer: Foe, Friend or Both?

Fusobacterium is a genus of anaerobic Gram-negative bacteria that has been increasingly implicated in a range of diseases, including periodontitis and cancer. This review critically evaluates the reported role of Fusobacterium nucleatum in cancer, highlighting new findings that suggest a more nuanced cross-talk with the disease. We contextualise current evidence on the interactions with the wider tumour micro-environment, including the roles of polymicrobial communities, microbial metabolites and taxonomic heterogeneity. Collectively, the evidence suggests that Fusobacterium nucleatum should not be regarded as universally pathogenic or oncogenic. Rather, its behaviour is likely context-dependent and shaped by its surrounding microenvironment. Notably, opposing pro- and anti-tumoural mechanisms can coexist within the same cancer type. For example, in colorectal cancer, F. nucleatum is predominantly associated with poorer outcomes by promoting immune evasion (e.g., suppression of cytotoxic T cell responses) and oncogenic signalling (e.g., via the E-cadherin/β-catenin pathway), yet it also displays oncosuppressive activity through promotion of neutrophil-mediated anti-tumoural cytotoxicity and butyrate-driven cytotoxic T cell activation and potentiation of immunotherapy. In head and neck cancer, by contrast, F. nucleatum detection is associated with improved survival across independent cohorts, potentially reflecting a different balance of these same competing mechanisms. We suggest implications for its proposed use as a biomarker and as a target in cancer therapy. Lingering questions are also laid out to help investigators shape future research to better capture the complexity of the TME and elucidate the overall impact of Fusobacterium nucleatum in cancer.