From oral dysbiosis to colorectal cancer: reframing fusobacterium nucleatum as an oxidative stress-primed oncobion

Here, we critically examine the existing evidence to offer a comprehensive and integrated perspective on F. nucleatum, exploring its role as an oncobiont that actively drives tumor progression, its value as a prognostic stratifier, and its potential as an emerging target for microbiota-informed precision oncology.Although Fusobacterium nucleatum is widely recognized as a colorectal cancer-associated oncobiont, current models still inadequately explain the biological transition from oral commensalism to colorectal pathogenicity. We propose that oxidative stress within the oral microenvironment represents the priming event that activates the pathogenic program of F. nucleatum prior to intestinal dissemination.Rather than providing a purely systematic overview, this opinion paper proposes a translational perspective in which oxidative stress acts as a critical ecological trigger capable of reshaping F. nucleatum pathogenicity and promoting inflammation-associated colorectal carcinogenesis. Within this framework, oxidative adaptation is interpreted as a dynamic contributor to bacterial persistence, tumor colonization, and therapy resistance.2 Background: what we already know Historically, F. nucleatum was classified into four subspecies (19), although recent genomic analyses demonstrated that these lineages represent distinct species (20). Among them, F. animalis is particularly enriched in CRC tissue (21). A landmark Nature study identified two major phylogenetic clades within F. animalis, C1 and C2, with C2 emerging as the dominant CRC-associated lineage, while C1 was later reclassified as F. watanabei (21,22). Importantly, the C2 clade exhibits enhanced acid resistance, adhesin expression, and tumor-colonizing capacity, promoting colorectal adenoma formation in murine models (21,23). These findings highlight the strain-specific pathogenic potential of the F. nucleatum complex and support the need for precision diagnostic and therapeutic approaches.F. nucleatum reaches the colorectal mucosa mainly through the oro-intestinal axis, either via gastrointestinal transit or hematogenous dissemination from the oral cavity (10). Genomic studies confirmed that oral and tumor-associated strains are often genetically identical, supporting the oral cavity as the primary reservoir for CRC colonization (12). Although rarely detected in healthy colonic microbiota, F. nucleatum is consistently enriched in CRC tissue (7,24). Three major adhesins mediate colonization and tissue tropism. FadA binds E-cadherin, activating β-catenin signaling and NF-κB inflammatory pathways while facilitating endothelial disruption and systemic dissemination (25,26). Fap2 mediates selective binding to tumor-associated Gal-GalNAc glycans and suppresses NK and T-cell activity through TIGIT interaction (27)(28)(29). Importantly, although direct mechanistic evidence remains limited, Fap2 interaction with FN1 deposited within the extracellular matrix may stabilize tumor colonization and immune evasion. Finally RadD contributes to biofilm organization and inhibits NKcell-mediated tumor killing through Siglec-7 binding (30,31), while also enhancing CRC colonization in vivo (32). Together, these findings indicate that tumor tropism and immune escape depend on coordinated adhesin activity rather than FadA alone, supporting the need for multi-target therapeutic strategies (33).One of the most intriguing advances in F. nucleatum research concerns the role of oxidative stress in driving the transition from commensal organism to oncogenic pathobiont. Scano et al. (34) developed an in vitro "Fusobacterium stress chamber" exposing clinical strains to sub-inhibitory H₂O₂ concentrations mimicking oral dysbiosis. Oxidative preconditioning significantly increased biofilm formation, dimethyl sulfide (DMS) production, and HT-29 colonization, with approximately doubled invasive capacity compared to unstressed strains (34). These findings suggest that oxidative stress directly enhances bacterial virulence before intestinal dissemination.Potential triggers of oral oxidative stress include pro-inflammatory diets, cigarette smoke (35), and H₂O₂containing antiseptic agents (34). Under these conditions, F. nucleatum acquires a more invasive phenotype characterized by increased adhesin expression, enhanced oxidative adaptation, and modulation of host inflammatory pathways.Importantly, oxidatively activated F. nucleatum increases pri-miR-155 while suppressing pri-miR-146a, promoting inflammation, tumor progression, and chemoresistance (34,(36)(37)(38). Simultaneously, ALDH2 upregulation may reduce intracellular malondialdehyde (MDA) accumulation, protecting CRC cells from oxidative cytotoxicity and further contributing to therapy resistance (34,39).Lastly Dadashi et al. (2021) demonstrated that the recombinant FadA adhesin from Fusobacterium nucleatum significantly promotes the proliferation of SW480 colorectal cancer cells in a dose-and time-dependent manner. These findings suggest that FadA may directly contribute to colorectal cancer progression by enhancing tumor cell growth, further supporting the involvement of F. nucleatum in colorectal carcinogenesis (40) Collectively, these findings support the hypothesis that oxidative stress acts as a biological priming event transforming F. nucleatum into an aggressive oncobiont before colorectal colonization.Over the past two years, our research group has increasingly focused on elucidating the mechanisms through which Fusobacterium nucleatum promotes inflammation and contributes to the establishment of a protumorigenic microenvironment. Particular attention has been devoted to the interplay between oxidative stress, inflammatory signaling, microbial colonization, and immune dysregulation in colorectal cancer and inflammatory bowel disease. The following sections summarize the main mechanistic and translational evidence currently supporting the emerging role of F. nucleatum in inflammation-driven colorectal carcinogenesis.As previously discussed, the adhesin FadA plays a central role in F. nucleatum-mediated colorectal carcinogenesis. In particular, FadA binding to E-cadherin activates β-catenin signaling and promotes proinflammatory and oncogenic pathways involved in tumor progression. The FadA/E-cadherin interaction activates β-catenin signaling, inducing transcription of oncogenic targets including cyclin D1, c-Myc, and MMP7 (15,41). This pathway promotes epithelial proliferation, cancer stem-cell phenotypes, and links chronic inflammation, particularly in inflammatory bowel disease (IBD), with increased CRC risk (6,15,41). FadA also contributes to genomic instability through Chk2 upregulation (42).In parallel, F. nucleatum activates the NLRP3 inflammasome, leading to caspase-1 activation and secretion of IL-1β and IL-18 (43). These cytokines sustain a pro-tumorigenic inflammatory microenvironment characterized by angiogenesis, epithelial-mesenchymal transition (EMT), immune evasion, and myeloid-cell recruitment (42,43). NLRP3 therefore emerges as a promising therapeutic target, particularly given the efficacy of novel aryl-sulfonamide inhibitors in preclinical models (44).Lipopolysaccharide (LPS)-mediated TLR2/TLR4-MyD88 activation further stimulates NF-κB and MAPK signaling, inflammatory cytokine production, anti-apoptotic proteins, EMT, autophagy, and resistance to 5fluorouracil and oxaliplatin (6,13,14). The same pathway promotes miR-21 upregulation and iron-dependent secretion of CCL8 and CXCL5, mechanisms associated with invasion, macrophage activation, and poor prognosis (14,(45)(46)(47)(48).F. nucleatum reshapes the CRC miRNA landscape through induction of oncogenic miRNAs, including miR-31 and oxidative stress-associated miR-155, while suppressing anti-inflammatory regulators such as miR-146a (49)(50)(51)(52). These alterations promote epithelial-mesenchymal transition (EMT), extracellular matrix degradation, metastatic dissemination, and resistance to apoptosis (54). Consistently, identical F. nucleatum strains have been identified in primary CRC lesions and liver metastases, supporting bacterial co-migration during metastatic spread (55,56). Importantly, F. nucleatum contributes to chemoresistance through interconnected inflammatory, autophagic, and redox-dependent pathways. TLR4/MyD88-mediated autophagy reduces sensitivity to 5-fluorouracil, while the E-cadherin/β-catenin/GPX4 axis suppresses ferroptosis and promotes oxaliplatin resistance (45,57). BIRC3 overexpression and exosome-mediated transfer of resistance-associated molecules further amplify antiapoptotic and chemoresistant phenotypes (58,59). Collectively, these mechanisms contribute to metastatic progression, systemic inflammation, and poor clinical outcome, consistent with the correlation between fecal F. nucleatum levels and circulating NET markers (60). The main biological mechanisms through which Fusobacterium nucleatum contributes to colorectal carcinogenesis are summarized in Table 1. The growing body of evidence linking Fusobacterium nucleatum to CRC and IBD suggests that this bacterium may represent more than a passive microbial biomarker of disease. Rather, F. nucleatum increasingly appears to function as a biologically active oncobiont capable of orchestrating chronic inflammation, epithelial transformation, immune escape, metastatic dissemination, and resistance to therapy through interconnected oxidative and inflammatory pathways (6,13,14,23).This concept is particularly relevant in chronic inflammatory disorders such as IBD, where persistent mucosal inflammation, epithelial barrier disruption, and oxidative stress create a permissive environment for bacterial colonization and tumorigenesis. Several studies have demonstrated that F. nucleatum abundance is significantly increased in both CRC and IBD tissues compared to healthy controls, supporting the existence of a shared pathogenic axis linking chronic inflammation and colorectal carcinogenesis (23,61).We argue that oxidative stress may represent the central mechanistic bridge connecting oral dysbiosis, chronic intestinal inflammation, neoplastic transformation, metastatic progression, and chemoresistance in F. nucleatum-associated disease. In this model, reactive oxygen species (ROS) generated by smoking, proinflammatory diets, periodontal inflammation, and intestinal inflammatory activity do not merely damage host tissues but actively reshape bacterial behavior, promoting the transition of F. nucleatum from commensal organism to aggressive pathobiont (34,35).Experimental evidence strongly supports this hypothesis. As discussed above, oxidative stress appears to play a central role in the pathogenic reprogramming of F. nucleatum. In support of this hypothesis, Scano et al. (34) demonstrated that H₂O₂ exposure enhances bacterial biofilm formation, invasiveness, dimethyl sulfide production, and colonization of HT-29 cells. (34,36,38).In our view, these findings support a broader biological paradigm in which oxidative stress acts as a "priming force" that enables F. nucleatum to acquire invasive, pro-inflammatory, and tumor-promoting capabilities before intestinal dissemination. Once established within the colorectal microenvironment, the bacterium further amplifies carcinogenesis through activation of β-catenin signaling, NLRP3 inflammasome activation, NF-κB-mediated cytokine production, and suppression of antitumor immunity (15,42,45). Importantly, these pathways are also deeply interconnected with extracellular matrix remodeling and metastatic progression.A particularly intriguing and potentially innovative aspect concerns the role of fibronectin 1 (FN1) within the tumor microenvironment. Traditionally considered a structural component of the extracellular matrix, FN1 may instead function as an active regulator of microbial tumor colonization. Emerging evidence suggests that the F. nucleatum adhesin Fap2 not only mediates binding to tumor-associated Gal-GalNAc glycans and TIGITdependent immune suppression but may also interact with FN1 deposited within CRC tissue, thereby stabilizing bacterial adhesion and persistence (27)(28)(29).Although direct mechanistic validation remains limited, emerging evidence supports a potential role for FN1 in stabilizing bacterial persistence within the tumor extracellular matrix. We propose that FN1 acts as an "ecological docking platform" facilitating selective bacterial colonization of the tumor niche. In this framework, the extracellular matrix is no longer a passive scaffold but an active participant in host-microbe interaction. The Fap2-FN1 axis may therefore represent a previously underrecognized microbial checkpoint controlling tumor tropism, immune escape, and metastatic dissemination. This hypothesis is particularly compelling because FN1 overexpression is itself associated with epithelial-mesenchymal transition (EMT), invasive behavior, and poor prognosis in CRC, suggesting a synergistic interaction between tumor matrix remodeling and microbial pathogenicity.Importantly, the biological effects of F. nucleatum appear to extend beyond tumor initiation and progression to include resistance to therapy. Multiple studies have demonstrated that F. nucleatum promotes resistance to 5-fluorouracil and oxaliplatin through activation of autophagy, suppression of ferroptosis, anti-apoptotic signaling, and oxidative stress modulation (13,46,57,58). These observations strongly suggest that bacterial colonization may directly influence treatment responsiveness and clinical outcome.Within this framework, the ongoing prospective translational clinical study proposed by Consolo et al. (42) assumes particular relevance. The study is designed to evaluate the relationship between F. nucleatum, oxidative stress biomarkers, inflammation, and chemoresistance in patients with CRC and IBD, with the aim of identifying biologically actionable pathways capable of guiding personalized therapeutic interventions (42). We believe that this approach may contribute to redefining the role of microbiomes in precision oncology.Indeed, if F. nucleatum actively contributes to tumor progression and resistance mechanisms, targeting the bacterium or its downstream inflammatory pathways could become a clinically meaningful therapeutic strategy. In this regard, NLRP3 inflammasome inhibitors represent particularly promising candidates. Pharmacological blockade of NLRP3 may simultaneously reduce chronic inflammation, reverse tumorpromoting cytokine signaling, and restore sensitivity to chemotherapy (42,44). Likewise, selective antimicrobial approaches directed against F. nucleatum, including narrow-spectrum antibiotics, bacteriophages, or adhesin-targeting strategies, may offer opportunities to reduce bacterial-driven carcinogenic signaling while preserving commensal microbiota integrity (23,33).From a preventive perspective, this concept may have even broader implications. If persistent F. nucleatum colonization contributes to the progression from chronic inflammation to neoplasia, particularly in high-risk populations such as IBD patients, microbiota-targeted interventions could potentially reduce long-term CRC risk. Although this hypothesis remains speculative and requires prospective validation, it introduces the provocative possibility that modulation of oncogenic bacteria may eventually become part of future cancer prevention strategies.Ultimately, we propose that the next frontier of precision oncology may not solely depend on tumor genomics, but also on the identification of microbiome-dependent inflammatory and oxidative pathways that shape tumor behavior and therapeutic response. In this context, F. nucleatum may represent one of the first clinically actionable microbial targets in colorectal cancer biology.Figure 1 presents a hypothetical conceptual framework linking oxidative stress adaptation of Fusobacterium nucleatum to colorectal carcinogenesis and microbiota-driven precision oncology. In conclusion the growing evidence linking Fusobacterium nucleatum to oxidative stress, chronic inflammation, immune escape, and chemoresistance supports a shift from purely tumor-centered oncology toward a microbiome-informed precision medicine framework (13,46,57,58,62).Current CRC screening strategies rely mainly on colonoscopy and fecal immunochemical testing (FIT), but these approaches insufficiently capture the biological mechanisms underlying inflammation-driven carcinogenesis. Combined salivary and fecal microbiota profiling may therefore represent a promising strategy, particularly since tumor-associated F. nucleatum strains are often genetically identical to those isolated from the oral cavity of the same patient (10,12). Stool-based quantification of F. nucleatum, especially when integrated with FIT and molecular biomarkers, already demonstrates encouraging diagnostic performance (63,64). Additional precision may derive from oxidative stress biomarkers such as MDA and 4-HNE (34,39), FN1 expression profiling, and identification of high-risk subtypes such as the F. animalis C2 clade (21,22,65). Collectively, these markers may support an integrated screening model capable of identifying high-risk individuals before overt neoplastic transformation occurs.Beyond diagnosis, F. nucleatum may also contribute to therapeutic stratification. Increasing evidence links bacterial colonization to resistance to chemotherapy and immunotherapy through TLR4/MyD88 signaling, autophagy activation, ferroptosis suppression, and modulation of the tumor immune microenvironment (13,46,57,58,62). In particular, patients with elevated intratumoral bacterial burden, oxidative stress activation, or NLRP3 upregulation may represent biologically distinct CRC subsets requiring alternative therapeutic approaches.Within this framework, microbiota-driven precision oncology could include prediction of oxaliplatin resistance, identification of patients less responsive to immunotherapy, and selection of candidates for microbiota-targeted interventions. Particularly promising are NLRP3-targeted strategies, which may simultaneously reduce inflammation, oxidative stress, and bacterial-driven carcinogenic signaling (42,44). Similarly, microbiota modulation through selective antibiotics, bacteriophages, probiotics, dietary interventions, and adhesin-targeting approaches may help reduce F. nucleatum-associated tumor promotion while preserving commensal microbiota balance (23,33).An equally important implication concerns cancer prevention. If oxidative stress acts as the biological trigger converting F. nucleatum from commensal bacterium into oncogenic pathobiont, then reduction of chronic oxidative stress may interfere with early carcinogenic activation. In this context, oral oxidative stress reduction may potentially contribute to preventive anti-oncogenic strategies. Smoking cessation, periodontal disease control, antioxidant-rich diets, and modulation of oral dysbiosis may therefore acquire a previously underappreciated role in CRC prevention, particularly in high-risk populations such as patients with IBD or chronic inflammatory disorders (34,56).Despite the rapidly expanding literature, important limitations remain. Most studies are heterogeneous in terms of sampling methods, microbiota analysis, and clinical endpoints, while the causal role of F. nucleatum in CRC progression still requires prospective validation. Furthermore, most available evidence remains associative, while prospective human studies demonstrating causal relationships between oxidative stress adaptation and CRC progression are still lacking. In this context, the ongoing prospective translational clinical study recently proposed by Consolo et al. (42) aims to integrate microbiota profiling, cytokine analysis, oxidative stress biomarkers, colonoscopic assessment, and CT-based radiomics in healthy subjects, IBD patients, and CRC patients. Colonoscopies and fecal sample collection are already underway, with the goal of clarifying whether F. nucleatum and oxidative stress-related pathways may serve not only as biomarkers of disease progression, but also as actionable targets for microbiota-driven precision oncology. Indeed, radiomics may potentially provide non-invasive surrogate markers associated with microbiota-driven tumor phenotypes.We argue that the next conceptual advance in microbiota-driven oncology will not derive merely from identifying tumor-associated microbes, but from understanding the environmental signals that convert commensals into oncogenic pathobionts. In this context, oxidative stress may represent the biological switch that transforms F. nucleatum from oral symbiont to colorectal oncobiont.There is a paucity of validated analytical methods in establishing microbiomebased biomarkers in clinical practice. Thus kitted and validated molecular methods with simple interpretation are much warranted for the clinical implementation of these microbiome based biomarkers.The future of precision oncology may require simultaneous targeting of tumor genomics, inflammatory signaling, and oncogenic microbiota ecosystems.