Exosome-Driven Epigenetic Rewiring in Cancer: Mechanisms and Clinical Implications

Small extracellular vesicles (sEVs), operationally referred to as exosomes, where strict biogenesis-based classification cannot be confirmed from the primary literature, are pivotal mediators of intercellular communication in cancer, transferring a diverse epigenetic payload that encompasses noncoding RNAs (ncRNAs), DNA fragments, chromatin-modifying enzymes, and metabolic effectors, which reprogram the recipient cell's chromatin architecture without altering the underlying DNA sequence. sEVs originating from tumors facilitate epigenetic modifications throughout the tumor microenvironment (TME), engaging stromal, immune, and vascular elements to support malignant development. This narrative review synthesizes mechanistic, preclinical, and translational evidence on sEVs-driven epigenetic regulation in cancer, focusing on how distinct cargo classes, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), DNA methyltransferases (DNMTs), and histone-modifying enzymes, drive chromatin remodeling, aberrant DNA methylation, transcriptional reprogramming, and acquired drug resistance in recipient cells. We further examine exosomal cargo signatures as minimally invasive liquid biopsy biomarkers and appraise engineered sEVs platforms for precision delivery of miRNA mimics, siRNAs, and small-molecule epigenetic inhibitors. Key methodological challenges, including EV isolation standardization, cargo validation, loading efficiency, in vivo biodistribution, and physiological concentration relevance, are critically evaluated, and a translational roadmap is proposed to guide reproducible clinical implementation of sEVs-mediated epigenetic cancer therapeutics.