Hepatocellular Carcinoma and the Multifaceted Relationship with Its Microenvironment: Attacking the Hepatocellular Carcinoma Defensive Fortress.

Simple Summary: The microenvironment of hepatocellular carcinoma is a really complex milieu, containing a wide variety of cells with specific tasks, belonging to both the mesenchimal and immunitary systems, the extracellular matrix, growth factors, proinflammatory cytokines, and translocated bacterial products. This intricate environment represents a source of potential targets in order to establish a wide and multitask therapeutic strategy for hepatocellular carcinoma. Hepatocellular carcinoma is a malignant tumor that originates from hepatocytes in an inflammatory substrate due to different degrees of liver fibrosis up to cirrhosis. In recent years, there has been growing interest in the role played by the complex interrelationship between hepatocellular carcinoma and its microenvironment, capable of influencing tumourigenesis, neoplastic growth, and its progression or even inhibition. The microenvironment is made up of an intricate network of mesenchymal cells, immune system cells, extracellular matrix, and growth factors, as well as proinflammatory cytokines and translocated bacterial products coming from the intestinal microenvironment via the enterohepatic circulation. The aim of this paper is to review the role of the HCC microenvironment and describe the possible implications in the choice of the most appropriate therapeutic scheme in the prediction of tumor response or resistance to currently applied treatments and in the possible development of future therapeutic perspectives, in order to circumvent resistance and break down the tumor's defensive fort. [ABSTRACT FROM AUTHOR]