Molecular mechanisms of tumor-associated macrophages in hepatocellular carcinoma development and therapy

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and ranks as the sixth most common cancer and the third leading cause of cancer-related death worldwide. Tumor-associated macrophages (TAMs) are predominant immune cells in the tumor microenvironment of HCC, playing critical roles in cancer cell proliferation, epithelial-mesenchymal transition, and metastasis. Reprogramming TAMs from a pro-tumoral phenotype to an anti-tumoral phenotype can enhance macrophage-mediated phagocytosis of HCC cells, improve cytotoxic T cell function, and increase the efficacy of immunotherapies. In this review, we summarize recent findings on how TAMs contribute to HCC development and progression, examine molecular markers and important signaling pathways that regulate TAM function within the tumor microenvironment, and discuss strategies for targeting TAMs at the cellular and molecular levels to treat HCC.

Keywords: Hepatocellular carcinoma; Macrophages; Immune checkpoint inhibitors; Immunotherapy; Signaling pathways

Core Tip: As a predominant population of immune cells in the tumor microenvironment, tumor-associated macrophages (TAMs) play an important role in the initiation and progression of hepatocellular carcinoma (HCC). TAM-derived factors, including but not limited to cytokines, chemokines, and exosomes, regulate angiogenesis, immunosuppression, and therapeutic resistance in HCC. Strategies such as reprogramming TAM polarization, suppressing immunosuppressive cell recruitment, and inhibiting immunosuppressive signaling pathways can decrease tumor-promoting immune cell recruitment, reinforce the cytotoxicity of T cells, and retard tumor cell proliferation, ultimately slowing or delaying tumor growth.