Roles of exosome-mediated macrophage polarization in the hepatocellular carcinoma progression

Abstract

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. The tumor microenvironment (TME) is a highly immunosuppressive niche shaped by aberrant angiogenesis, chronic inflammation, and extracellular matrix remodeling, which facilitates immune evasion and promotes HCC proliferation, invasion, and metastasis. Tumor-derived exosomes act as critical mediators of intercellular communication, delivering bioactive cargo such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) to macrophages, thereby modulating their polarization and functional state. Specifically, exosomal signals induce M2 macrophage polarization, promoting tumor progression, immune suppression, and metastatic dissemination, whereas M1 macrophage polarization enhances antitumor immunity via activation of cytotoxic T cells and pro-inflammatory signaling. Key regulatory pathways include STAT3 activation and NF-κB signaling, which govern exosome-mediated macrophage reprogramming and cytokine release, further modulating the TME. This review summarizes the current insights into exosome-driven macrophage polarization in HCC, providing a potential immunotherapeutic strategy for restoring antitumor immunity and improving HCC patient prognosis.