Tumor-associated macrophages in hepatocellular carcinoma: Cellular plasticity and therapy resistance in crosstalk

Hepatocellular carcinoma (HCC) is the predominant type of liver cancer. There are different risk factors for HCC including viral infection, liver fibrosis, non-alcoholic fatty liver disease, environmental factors and genomic alterations. The tumor microenvironment (TME) has been proposed as a potent regulator of tumor malignancy comprised of normal and cancerous cells. Macrophages are among the most abundant cells in the TME, known as tumor-associated macrophages (TAMs) that can control proliferation, metastasis, immune reactions and therapy response of tumor cells. In the present review, the function of TAMs in the regulation of HCC progression was evaluated. TAMs are prognostic factors in HCC that increase in TAM infiltration into TME can cause undesirable outcome in patients. Moreover, M2 polarization of macrophages can impair function of other immune cells such as T cells and natural killer cells to mediate immune evasion. TAMs demonstrate association with other biological events including autophagy and glycolysis. There is mutual interaction between TAMs and exosomes that TAM-mediated exosome secretion regulates HCC progression, while exosomes derived from other cells can also affect TAMs. Inhibition of macrophage recruitment, their depletion and increasing M1 polarization are promising approaches in HCC therapy. The natural products and nanostructures have been also recently introduced for the regulation of macrophages in HCC therapy.