Role of Exosomes in Immunotherapy of Hepatocellular Carcinoma

SIMPLE SUMMARY: Hepatocellular carcinoma is one of the most lethal malignancies, having a significantly poor prognosis. Immunotherapy, as an emerging tumor treatment option, provides new hope for many cancer patients. However, a large proportion of patients do not benefit from immunotherapy. As a critical cell-to-cell communication mediator in the tumor immune microenvironment, exosomes may play a unique role in hepatocellular carcinoma immune response and thus affect the efficiency of immunotherapy. In this review, we discuss related research on the roles of exosomes in the current immunotherapy resistance mechanism of hepatocellular carcinoma. Furthermore, we also clarify the excellent predictive value of exosomes and the roles they play in improving immunotherapy efficacy for hepatocellular carcinoma patients. We hope that our review can help readers to gain a more comprehensive understanding of exosomes’ roles in hepatocellular carcinoma immunotherapy. ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, having a significantly poor prognosis and no sufficiently efficient treatments. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has provided new therapeutic approaches for HCC patients. Nevertheless, most patients with HCC do not benefit from immunotherapy. Exosomes are biologically active lipid bilayer nano-sized vesicles ranging in size from 30 to 150 nm and can be secreted by almost any cell. In the HCC tumor microenvironment (TME), numerous cells are involved in tumor progression, and exosomes—derived from tumor cells and immune cells—exhibit unique composition profiles and act as intercellular communicators by transporting various substances. Showing the dual characteristics of tumor promotion and suppression, exosomes exert multiple functions in shaping tumor immune responses in the crosstalk between tumor cells and surrounding immune cells, mediating immunotherapy resistance by affecting the PD-1/PD-L1 axis or the anti-tumor function of immune cells in the TME. Targeting exosomes or the application of exosomes as therapies is involved in many aspects of HCC immunotherapies (e.g., ICIs, tumor vaccines, and adoptive cell therapy) and may substantially enhance their efficacy. In this review, we discuss the impact of exosomes on the HCC TME and comprehensively summarize the role of exosomes in immunotherapy resistance and therapeutic application. We also discuss the potential of exosomes as biomarkers for predicting the efficacy of immunotherapy to help clinicians in identifying HCC patients who are amenable to immunotherapies.