Fig. 3: The transition of the liver microenvironment contributes to HCC development.

Stimulation by liver injury/damage can induce Kupffer cells to produce proinflammatory cytokines and TGF-β. The migration of immune cells is induced by the proinflammatory response. The proinflammatory immune response can increase Th17 cell differentiation. TGF-β can promote the activation of HSCs, contributing to collagen fiber production and the development of hepatic cirrhosis. In hepatic cirrhosis, the anti-inflammatory response is increased. Increasing Th2 cell differentiation can induce the M2-like transition of macrophages. Activated HSCs can induce the development of MDSCs as well as immature DCs. Increased TGF-β can induce EMT in hepatocytes. Chronic liver inflammation can induce the dedifferentiation of hepatocytes. Hypoxia caused by hepatic cirrhosis and angiogenesis can constitute the protumoral liver microenvironment.