Kupffer cells and monocyte-derived macrophages in the pathogenesis and treatment of hepatocellular carcinoma

Kupffer cells, the resident liver macrophages, are characterized by self-renewal capacity and extensive plasticity. Kupffer cells are involved in the regulation of several liver functions such as the maintenance of liver tolerance against antigens arriving at the liver through the portal vein, the autophagy and apoptosis of hepatocytes and other liver sinusoidal cells.and various metabolic functions such as iron homeostasis and lipid metabolism. In acute liver injury, Kupffer cells are involved in both liver damage and resolution. During chronic liver injury, resident and bone marrow-derived macrophages drive either the progression or resolution of fibrosis and cirrhosis. Inevitably, they are implicated in the initiation, progression or defense against hepatocellular carcinoma (HCC) as members of the tumor microenvironment together with bone marrow-derived macrophages. The present review describes the heterogeneity of Kupffer cells and liver-infiltrating macrophages, their functions and their participation in liver cancer with particular emphasis on factors modulating their pro-tumoral and anti-tumoral differentiation. The review is further focused on their involvement in HCC as they participate in the population of tumor-associated macrophages. Finally, the potential use of Kupffer cells and macrophages for the treatment of HCC, including the potentiation of immune checkpoint inhibitors, is presented.