Gut microbiota in esophageal cancer: mechanisms, clinical implications, and therapeutic potential

Abstract

Esophageal cancer (EC) is a highly prevalent and aggressive gastrointestinal malignancy. Late diagnosis and heterogeneous responses to chemoradiotherapy and immune checkpoint inhibitor (ICI) therapies severely challenge clinical management. Accumulating evidence suggests that gut microbiota dysbiosis influences esophageal mucosal malignant transformation, tumor progression, and therapeutic outcomes through the gut-esophageal axis. However, most existing research remains correlational. To bridge this gap, this review critically synthesizes the dysbiosis signatures of EC and establishes a five-tier evidence grading framework to rigorously distinguish causal mechanisms from preclinical inferences. This microbial regulation is predominantly driven by metabolite-mediated signaling, remodeling of the tumor immune microenvironment (TME), intestinal barrier disruption, and oncogenic pathway activation. We functionally classify EC-associated dysbiosis into pro-tumorigenic, anti-tumorigenic, and context-dependent taxa, emphasizing a multidimensional ecosystem perspective. Furthermore, we evaluate the utility of gut microbial signatures as predictive biomarkers for neoadjuvant therapy and prognosis. Microbiota-targeted intervention strategies, including fecal microbiota transplantation (FMT), microecological preparations, and Traditional Chinese Medicine (TCM), have entered clinical exploration as adjunctive approaches to optimize treatment efficacy. Finally, we address current translational barriers and propose future directions, emphasizing multi-omics integration, spatial transcriptomics, and artificial intelligence (AI). This provides an objective, mechanistically grounded framework for advancing microbiota-guided personalized oncology in EC.