The tumor microenvironment (TME) is an essential intrinsic portion of hepatocellular carcinoma (HCC) for the regulation of its origination, development, invasion, and metastasis. As emerging components of the tumor-host interaction, exosomes are increasingly recognized as professional carriers of information in TME and as pivotal molecular entities involved in tumorigenic microenvironment setup. However, much remains unknown about the role of the exosome communication system within TME in the development and progression of HCC. In this review, we focus on the roles and probable mechanisms of TME in HCC and show the exosome-based immune regulation in TME to promote HCC. Multiple processes are involved in HCC, including tumor survival, growth, angiogenesis, invasion, and metastasis. We also discuss the specific roles of exosomes in HCC processes by molding hospitable TME for HCC, such as providing energy, transmitting protumor signals, and evading inhibitory signals. In addition, exosomes induce angiogenesis by changing the biological characteristics of endothelial cells and directly regulating proangiogenic and propermeability factors. Furthermore, exosomes may lead to HCC metastatic invasion by epithelial-mesenchymal transformation, extracellular matrix degradation, and vascular leakage. Finally, we summarize the therapeutic usage of exosomes in the HCC microenvironment and attempt to provide a theoretical reference for modern antitumor agents designed to target these mechanisms.

The negative regulators in the interferon (IFN) signaling pathway inhibit intrahepatic immune response, resulting in suboptimal therapeutic response to IFNα treatment in chronic hepatitis B (CHB) patients. Identifying the key negative factors and elucidating the regulating mechanism are essential for improving anti‐HBV (hepatitis B virus) efficacy of IFNα. From the Gene Expression Omnibus (GEO) database, we downloaded and analyzed gene expression profiles of CHB patients with different responses to IFNα (GSE54747), and found that innate immune status was associated with the IFNα‐based therapeutic response in CHB patients. Through PCR array, we found higher baseline level of IFN‐induced transmembrane protein 2 (IFITM2) mRNA and lower baseline level of IFNα mRNA in peripheral blood mononuclear cells (PBMCs) of CHB patients with suboptimal response to IFNα treatment. Increased IFITM2 protein was also found in the serum of IFNα nonresponsive patients. With further experiments, we found that overexpressing IFITM2 in Huh7 cells suppressed endogenous IFNα synthesis by inhibiting phosphorylation of extracellular signal–regulated kinase (ERK), TANK‐binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3); knocking out IFITM2 enhanced activation of the endogenous IFNα synthesis pathway, exhibiting better inhibition on HBV replication. We also found that IFITM2 protein was shuttled by exosomes to dendritic cells (DCs), the main source of endogenous IFNα. Exosome‐mediated transport of IFITM2 inhibited synthesis of endogenous IFNα in DCs whereas the inhibitory effect was abolished when IFITM2 was knocked out. Furthermore, we demonstrated that both palmitoylation inhibitor and mutation on 70/71 sites of IFITM2 protein influenced its incorporation into exosomes. Mutated IFITM2 protein increased the effect of IFNα against HBV. Conclusion: Exosome‐mediated transport of IFITM2 to DCs inhibits IFNα pathway activation and blocks anti‐HBV efficacy of exogenous IFNα. The findings provide an explanation to the suboptimal response of CHB patients to IFNα treatment.

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Hepatitis viruses are chief pathogens of hepatitis and end-stage liver diseases. Their replication and related pathogenic process highly rely on the host micro-environment and multiple cellular elements, including exosomes. Representing with a sort of cell-derived vesicle structure, exosomes were considered to be dispensable cellular components, even wastes. Along with advancing investigation, a specific profile of exosome in driving hepatitis viruses’ infection and hepatic disease progression is revealed. Exosomes greatly affect the pathogenesis of hepatitis viruses by mediating their replication and modulating the host immune responses. The characteristics of host exosomes are markedly changed after infection with hepatitis viruses. Exosomes released from hepatitis virus-infected cells can carry viral nucleic or protein components, thereby acting as an effective subterfuge for hepatitis viruses by participating in viral transportation and immune escape. On the contrary, immune cell-derived exosomes contribute toward the innate antiviral immune defense and virus eradication. There is growing evidence supporting the application of exosomal biomarkers for predicting disease progress or therapeutic outcome, while exosomal nanoshuttles are regarded as promising therapeutic options based on their delivery properties and immune compatibility. In this review, we summarize the biogenesis and secretion mechanism of exosomes, review the recent findings pertaining to the role of exosomes in the interplay between hepatitis viruses and innate immune responses, and conclude their potential in further therapeutic application.