Liver microenvironment and therapy resistance in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains a critical health concern due to its late diagnosis, therapy resistance, high mortality rate, and, more importantly, its high recurrence rate. Currently, despite the development of various treatment modalities such as immunotherapy and targeted therapies, chemotherapy continues to be the most common therapeutic approach for advanced stages of HCC. Tumor cells are surrounded by a tumor microenvironment (TME), which consists of various types of immune and non-immune cells embedded within a dynamic extracellular matrix (ECM). Despite the application of different innovative therapies, the heterogeneous nature of tumor cells within the microenvironment can lead to therapy resistance against chemotherapy or other therapeutic protocols. The active nature of the ECM, influenced by its structural components and embedded cytokines, can alter its formation in a way that favors resistance to therapeutic agents. Several changes in the physical condition of the TME, such as fluid flow rate, shear stress, pH, hypoxia, and stiffness, may induce resistance to treatment in HCC cells. In this paper, we summarize recent research progress related to the TME of HCC and its contribution to drug resistance. This aims to provide clearer insights into the TME and its role in HCC drug resistance.