Association between intratumoral <i>Fusobacterium nucleatum</i> levels and clinical outcomes in esophageal squamous cell carcinoma: A comprehensive systematic review.

Abstract

e16081 Background: Intratumoral Fusobacterium nucleatum (F. nuc) is a key microbial participant in gastrointestinal malignancy progression. In esophageal squamous cell carcinoma (ESCC), the link between bacterial colonization and metastatic potential requires characterization. This systematic review synthesizes evidence from independent cohorts to define the relationship between bacterial DNA load, molecular pathways driving metastasis, and survival. Methods: PubMed, EMBASE, and Cochrane databases were searched for studies till January 2026 evaluating F. nuc and ESCC prognosis using quantitative DNA-based assays (qPCR or 16S rRNA sequencing). Multivariate-adjusted hazard ratios (HR) for cancer-specific survival (CSS) and disease recurrence were pooled using a Random Effects Model; heterogeneity was assessed by I^2. Synthesis identified technical/geographic consistencies and correlations with pathological markers of tumor invasion and lymph node spread. Results: Eight studies from China and Japan met inclusion criteria. High intratumoral F. nuc load was a significant independent prognostic factor. Elevated DNA load was a robust predictor of poor outcomes, specifically associated with a CSS HR of 1.78 (95% CI 1.06-2.65). Recurrence risk was similarly elevated, yielding a pooled Relapse-Free Survival (RFS) HR of 1.71 (95% CI 1.27-2.30,I^2 = 0).Findings remained stable across multicenter registries in Japan and China, likely due to standardized qPCR targeting nusG or 16S rRNA genes. Qualitatively, high DNA load correlated with advanced pT stage and lymph node metastasis. This phenotype is mediated by TLR4/NF-κB and NOD1/RIPK2 signaling, which drive epithelial-mesenchymal transition (EMT) and foster an immunosuppressive "cold" tumor microenvironment characterized by M2-like macrophage and regulatory T-cell recruitment. Conclusions: Intratumoral F. nuc DNA quantification identifies a high-risk biological subtype of ESCC. Consistency across regional cohorts indicates F. nuc is a universal driver of metastatic progression in squamous cell pathology. Standardized microbial DNA quantification may serve as a high-fidelity biomarker to refine risk stratification and guide microbiota-targeted neoadjuvant strategies to mitigate metastatic spread in ESCC.