Extracellular vesicles as systems-level regulators of tumor progression: Integrating signaling networks, microenvironment reprogramming, and therapy resistance.

Extracellular vesicles (EVs), once considered cellular debris, are now recognized as critical mediators of intercellular communication that regulate multiple aspects of tumor progression. Rather than acting through isolated pathways, EVs function as system-level regulators integrating intercellular signalling networks, cargo sorting mechanisms and tumor microenvironmental cues to coordinate dynamic and interconnected oncogenic responses. Unlike previous reviews that discuss these processes individually, this review adopts an integrative system-level framework linking EV-mediated oncogenic signaling, microenvironmental remodeling, angiogenesis, premetastatic niche formation, and therapy resistance that can lead to tumor progression. Accumulating evidence highlights EVs as systems-level regulators that integrate oncogenic signaling, microenvironmental remodeling, and adaptive tumor responses. This review presents a mechanistically focused overview of EV biology, moving beyond descriptive aspects of biogenesis to emphasize its functional roles in coordinating cancer progression. EVs facilitate the transfer of bioactive cargo, including proteins, nucleic acids, and lipids, thereby modulating key oncogenic signaling pathways such as PI3K/Akt, Wnt/β-catenin, and TGF-β, which collectively drive proliferation, invasion, and cellular plasticity. In addition, EVs play a pivotal role in reprogramming the tumor microenvironment by promoting angiogenesis, stromal activation, immune modulation, and pre-metastatic niche formation. Emerging evidence further implicates EVs in therapy resistance, where they contribute to drug efflux and the horizontal transfer of resistance-associated molecules. The functional heterogeneity of EV subpopulations and their context-dependent roles are also discussed as key determinants of disease progression. From a translational perspective, EVs are increasingly explored as minimally invasive biomarkers for cancer diagnosis and prognosis, as well as versatile platforms for targeted drug delivery. However, challenges related to isolation techniques, standardization, and clinical scalability remain significant barriers to their implementation. Collectively, this review provides a systems-level perspective on EV-mediated communication networks in cancer, underscoring their dual role as central drivers of tumor progression and promising targets for therapeutic intervention.