Abstract
Gastrointestinal (GI) cancers remain a leading global cause of cancer-related mortality, significantly impacting public health and healthcare systems worldwide. Emerging evidence underscores the critical role of gut microbiome dysbiosis-characterized by disrupted microbial diversity and function-in GI carcinogenesis. Utilizing recent advancements in multi-omics technologies and sophisticated computational biology, researchers have elucidated distinct microbial signatures associated with colorectal, gastric, hepatobiliary, pancreatic, and esophageal cancers. This review comprehensively analyzes the primary mechanisms through which gut microbes contribute to cancer development and progression, encompassing genotoxicity, chronic inflammation, metabolic dysregulation, epigenetic modifications, and immunomodulation. Moreover, we explore innovative microbiome-derived biomarkers for potential clinical applications, including early diagnosis, prognosis assessment, and therapeutic response prediction. The intricate interactions between microbiota and standard cancer therapies-chemotherapy, immunotherapy, and radiation therapy-are discussed, highlighting microbiome influences on therapeutic efficacy and adverse effect profiles. We also critically assess the impact of modifiable factors such as diet, medications, lifestyle, and environmental exposures on microbiome composition and cancer risk. The review evaluates emerging therapeutic interventions, including dietary modifications, probiotics, prebiotics, fecal microbiota transplantation (FMT), and engineered live biotherapeutics. Despite notable advancements, significant hurdles remain, including clarifying causality, methodological standardization, and equitable global research representation. Addressing these challenges, we propose a strategic research agenda aimed at harnessing microbiome insights to advance precision oncology and improve GI cancer outcomes globally.