Extracellular vesicles as modulators of cancer metabolism and microenvironment

The existence of small vesicles released by cells into the extracellular space was first documented over 40 years ago. These nanoparticles, now recognized as extracellular vesicles (EVs), were originally defined as "cellular dust" reflecting the early belief that their primary function was to dispose of cellular waste. Nowadays, it is widely acknowledged that EVs make a fundamental contribution to intercellular communication, being capable of transporting biologically active molecules, including proteins and nucleic acids, which regulate both physiological and pathological processes. Their involvement in various diseases, particularly cancer, has been well documented. EVs influence tumor development, progression, and therapeutic response, and have therefore been considered potential diagnostic and prognostic biomarkers. In this review, we focus on the contribution of EVs in modulating tumor cell metabolism and the tumor microenvironment. Specifically, we describe how EVs promote angiogenesis, induce the transformation of fibroblasts into cancer-associated fibroblasts, and influence extracellular matrix remodeling. Additionally, we explore their contribution to the reprogramming of tumor metabolism, including glycolytic, lipid, and amino acid pathways. We provide an in-depth overview of the key molecules carried by EVs that contribute to these pro-tumorigenic effects and of the underlying mechanisms involved.