Exosomal Non-Coding RNAs: Emerging regulators of the tumor microenvironment in gastrointestinal and hepatobiliary cancers.
Extracellular vesicle (EV)-associated non-coding RNAs (ncRNAs) are increasingly recognized as mediators of intercellular communication within the tumor microenvironment (TME), yet their mechanistic and translational significance varies substantially across gastrointestinal and hepatobiliary cancers. This narrative review, informed by a structured literature search, integrates evidence on EV-associated microRNAs, long non-coding RNAs, and circular RNAs in esophageal, gastric, colorectal, pancreatic, hepatocellular carcinoma, and cholangiocarcinoma. Rather than organizing the literature by RNA class or individual tumor type, we synthesize findings according to major TME functions, including immune remodeling, cancer-associated fibroblast activation, vascular remodeling, paracrine tumor-cell reprogramming, therapy resistance, and tumor-suppressive vesicular signaling. Recurrent mechanisms involve PTEN/PI3K/AKT, JAK/STAT, TGF-β/Smad, Wnt/β-catenin, and immune-checkpoint pathways, but the strength of evidence differs markedly among studies. Accordingly, mechanistic findings are distinguished from animal-model-supported, clinically correlated, preliminary, and biomarker-only evidence using a standardized descriptive framework. The review also highlights cholangiocarcinoma as an underrepresented but increasingly informative hepatobiliary model while avoiding generalization to broader biliary tract cancers when direct evidence is lacking. Major barriers to clinical translation include inconsistent EV isolation and characterization, uncertain vesicle-source attribution, limited validation of recipient-cell transfer and causal targets, small retrospective cohorts, and insufficient prospective validation. Overall, EV-ncRNAs represent promising mechanistic biomarkers and therapeutic targets, but rigorous source-specific validation and standardized analytical workflows are required before clinical implementation.