Exosomal Non‐Coding RNAs in Gastrointestinal Cancer Drug Resistance: A Systematic Review of Emerging Mechanisms and Clinical Implications

Gastrointestinal (GI) tumours are one of the most prevalent cancers globally. Even with normal GI function, individuals may develop neoplasms, highlighting the need to better understand the underlying causes of tumorigenesis. The emergence of tumour drug resistance represents the main reason for the failure of drug treatment; thus, it is imperative to investigate all the potential mechanisms of this very complex phenomenon. It is significant that exosomes and noncoding RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), originating from tumour cells, are linked to both GI drug resistance and the carcinogenesis and development of GI disease. Thus, we propose a systematic review of the literature to provide an overview of the current landscape concerning exosomal ncRNAs as diagnostic and prognostic biomarker resources in resistant GI cancer. We performed the current systematic review according to PRISMA guidelines and comprehensively explored PubMed, Web of Science, Scopus and Google Scholar databases to achieve the article search. Seventy-six studies were included in the investigation, comprising 50 cohort studies and 26 nested case-control studies (between 1994 and 2025). Among all systematically reviewed exosomal ncRNAs, we primarily found molecules with prognostic significance and predictive relevance, and those that serve both purposes have been identified. Furthermore, among all analysed ncRNAs isolated from exosomes, miRNAs, lncRNAs and circRNAs have emerged as the most extensively studied and are proposed as potential tools for predicting resistance or sensitivity to GI cancer treatments. Our analysis offers a comprehensive overview of the current landscape concerning exosomal ncRNAs as potential clinical biomarkers for resistant GI tumours. However, despite extensive research efforts, the application of exosomal biomarkers in GI cancers is still in its infancy. None of the identified exosomal biomarkers have advanced beyond preclinical studies, and their applicability in clinical settings remains limited, largely due to challenges in clinical validation, standardisation and biomarker specificity.