Current Strategies for the Treatment of Hepatocellular Carcinoma by Modulating the Tumor Microenvironment via Nano-Delivery Systems: A Review

Liver cancer remains a global health challenge with a projected incidence of over one million cases by 2025. Hepatocellular carcinoma (HCC) is a common primary liver cancer, accounting for about 90% of all liver cancer cases. The tumor microenvironment (TME) is the internal and external environment for tumor development, which plays an important role in tumorigenesis, immune escape and treatment resistance. Knowing that TME is a unique setting for HCC tumorigenesis, exploration of strategies to modulate TME has attracted increasing attention. Among them, the use of nano-delivery systems to deliver therapeutic agents to regulate TME components has shown great potential. TME-modulating nanoparticles have the advantages of protecting therapeutic agents from degradation, enhancing the ability of targeting HCC and reducing systemic toxicity. In this article, we summarize the TME components associated with HCC, including cancer-associated fibroblasts (CAFs), extracellular matrix (ECM), endothelial cells and immune cells, discuss their impact on the HCC progression, and highlight recent studies on nano-delivery systems that modulate these components. Finally, we also discuss opportunities and challenges in this field.