Early esophageal squamous neoplasia and the microbiome: evidence, mechanisms, and early-detection potential
Esophageal squamous cell carcinoma (ESCC) remains a major cause of cancer mortality, largely because most patients are diagnosed at an advanced stage. High-grade intraepithelial neoplasia (HGIN) represents an important and clinically actionable precancerous stage in the ESCC pathway, during which timely detection and endoscopic therapy can be curative. However, population screening with endoscopy is resource-intensive and has limited acceptability. Accumulating observational evidence suggests that ESCC and its precancerous stages are accompanied by alterations in the esophageal, oral, and tumor-associated microbiome, although the reproducibility and clinical significance of these findings vary across cohorts, sample types, and analytical methods. These microbial changes are shaped by shared risk factors, including smoking, alcohol consumption, hot beverages, poor oral hygiene, local mucosal injury and host immunity. Dysbiosis involves not only bacteria but also fungi and cross-kingdom interactions, which may be associated with barrier disruption, chronic inflammation, and malignant transformation. In this review, we summarize current evidence on the bacteriome and mycobiome across the normal squamous mucosa-HGIN-ESCC, focusing on microbial candidates, potential host–microbe mechanisms, and early-detection relevance. We also discuss saliva-based testing, non-endoscopic esophageal sampling, blood-derived microbial signals, and AI-assisted risk models. At present, microbiome-based biomarkers should be regarded as promising but not yet clinically implementation-ready tools. Further longitudinal validation, standardized methodology, and external cohort testing are required before they can be integrated into routine ESCC early-detection or risk-stratification pathways.