Cancer-associated fibroblast-derived exosomes in cancer progression: a focus on hepatocellular carcinoma

The tumor microenvironment (TME) has drawn much interest recently in the search for innovative cancer therapeutics, especially in light of the growing body of evidence supporting the efficacy of immune checkpoint inhibitors (ICIs). The TME comprises various cell types within the extracellular matrix (ECM), such as immune cells, endothelial cells, and cancer-associated fibroblasts (CAFs). Throughout the malignancy, these cells interact with cancerous cells and with one another. Inside the TME, CAFs are predominant and diverse cell types essential in regulating immune escape, angiogenesis, chemotherapeutic resistance, and cancer cells to invade and metastasize. Extracellular vesicles (EVs) and soluble substances are secreted by CAFs, which also remodel the extracellular matrix to partially coordinate their actions. A subclass of EVs called exosomes comprises proteins, lipids, and nucleic acids. Exosomes contain macromolecules that can transfer from one cell to another, changing the recipient cell's activity. Since exosomes are also circulating, it is possible to investigate their composition as potential biomarkers for cancer patient's diagnosis and prognosis. In this review, we focus on the function of exosomes derived from CAFs in the communications between CAFs and other TME cells and cancerous cells. Initially, we explain the various roles of CAFs in carcinogenesis. Subsequently, we address the processes by which CAFs interact with hepatocellular carcinoma (HCC) cells and other cells within the TME, with a special focus on the function of exosomes. We then go into greater detail regarding the processes by which exosomes derived from CAFs aid in the development of HCC, in addition to the clinical implications of exosomes. Finally, we address facets of exosomes that warrant additional research, such as novel discoveries regarding the enhancement of immune checkpoint inhibitor blockade therapy.