Overcoming the therapeutic resistance of hepatomas by targeting the tumor microenvironment

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and is the third leading cause of cancer-related mortality worldwide. Multifactorial drug resistance is regarded as the major cause of treatment failure in HCC. Accumulating evidence shows that the constituents of the tumor microenvironment (TME), including cancer-associated fibroblasts, tumor vasculature, immune cells, physical factors, cytokines, and exosomes may explain the therapeutic resistance mechanisms in HCC. In recent years, anti-angiogenic drugs and immune checkpoint inhibitors have shown satisfactory results in HCC patients. However, due to enhanced communication between the tumor and TME, the effect of heterogeneity of the microenvironment on therapeutic resistance is particularly complicated, which suggests a more challenging research direction. In addition, it has been reported that the three-dimensional (3D) organoid model derived from patient biopsies is more intuitive to fully understand the role of the TME in acquired resistance. Therefore, in this review, we have focused not only on the mechanisms and targets of therapeutic resistance related to the contents of the TME in HCC but also provide a comprehensive description of 3D models and how they contribute to the exploration of HCC therapies.

Automated summary

Hepatocellular carcinoma is the main type of liver cancer and the third leading cause of cancer-related deaths worldwide. The constituents of the tumor microenvironment may explain the mechanisms of therapeutic resistance in HCC, but the heterogeneity of the microenvironment makes treatment more challenging. Three-dimensional organoid models also play an important role in the study of HCC therapies.