Tumor-Associated Macrophages in Hepatocellular Carcinoma: Friend or Foe?

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and it has diverse etiologies with multiple mechanisms. The diagnosis of HCC typically occurs at advanced stages when there are limited therapeutic options. Hepatocarcinogenesis is considered a multistep process, and hepatic macrophages play a critical role in the inflammatory process leading to HCC. Emerging evidence has shown that tumor-associated macrophages (TAMs) are crucial components defining the HCC immune microenvironment and represent an appealing option for disrupting the formation and development of HCC. In this review, we summarize the current knowledge of the polarization and function of TAMs in the pathogenesis of HCC, as well as the mechanisms underlying TAM-related anti-HCC therapies. Eventually, novel insights into these important aspects of TAMs and their roles in the HCC microenvironment might lead to promising TAM-focused therapeutic strategies for HCC.

Keywords: Cancer therapy; Epigenetic modification; Hepatocellular carcinoma; Macrophage polarization; Tumor-associated macrophages.

Fig. 1

A schematic diagram depicting the disparate origins and phenotypes of heterogeneous macrophages in hepatocellular carcinoma (HCC). HCC is one of the deadliest cancers worldwide, and liver fibrosis is a key factor in the development of HCC. Chronic liver injury due to different etiologies, including lipopolysaccharide (LPS), CCl4, a diet rich in fat/alcohol, diethylnitrosamine (DEN) and others, leads to liver fibrosis that can ultimately develop into HCC. Hepatic macrophages (infiltrated macrophages and resident Kupffer cells [KCs]) originate from fetal yolk sac and infiltrated hematopoietic stem cells (HSCs)/bone marrow-derived monocytes. Emerging evidence suggests the pivotal role of heterogeneous macrophages in the development of liver injury, fibrosis and HCC. The predominant M1 macrophages in liver fibrosis could be reprogrammed into M2-activated phenotypes in response to stimuli from the tumor microenvironment. We propose that tumor-associated macrophages may represent a target for the prevention or treatment of HCC. IFN-γ, interferon-γ; IL, interleukin; GC, glucocorticoid hormones; GM-CSF, granulocyte-macrophage colony stimulating factor; M-CSF, macrophage colony-stimulating factor; TLR, Toll-like receptor; TNF, tumor necrosis factor.

Fig. 2

Tumor-associated macrophages (TAMs) correlate with resistance to chemotherapy and molecular-targeted therapy in hepatocellular carcinoma (HCC). Chemotherapy and molecular-targeted therapy play critical roles in the treatment of HCC; however, tumor resistance frequently emerges during these therapeutic processes. Considerable evidence has shown that M2 TAMs are closely associated with therapeutic resistance. Targeting TAM infiltration and polarization in the HCC tumor microenvironment might result in significant antitumor activity in chemotherapy and molecular-targeted therapy for HCC. AKT, protein kinase B (PKB); CCL, chemokine ligand; CCR2, CC motif chemokine receptor–2; CKI, compound Kushen injection; c-Met, hepatocyte growth factor receptor; ERK1/2, extracellular signal-regulated kinase 1/2; EMT, epithelial to mesenchymal transition; HGF, hepatocyte growth factor; HIF, hypoxia-inducible factor; HMGB1, high mobility group box 1; IL, interleukin; JAK2, Janus kinase 2; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; Snail2, a zinc finger transcription factor 2; STAT3, signal transducer and activator of transcription 3; TANs, tumor-associated neutrophils; TAZ, transcriptional coactivator with PDZ-binding motif; Treg, regulatory T cell; YAP, yes-associated protein.

Fig. 3

Functional characterization of tumor-associated macrophages (TAMs) in hepatocellular carcinoma (HCC) radiotherapy. Irradiation in patients with HCC largely prevents tumor growth and causes a continuous influx of recruited F4/80+CD68+ (M1) macrophages into the irradiated tumors. Emerging evidence suggests the efficacy of radiotherapy when used in combination with different existing therapies, including recombinant macrophage inflammatory protein-1 α (MIP-1α), zoledronic acid and immune checkpoint inhibitors (ICIs), for the treatment of metastatic HCC. These results show that targeting TAM infiltration and function potentiates the anti-liver cancer effects of radiotherapy. CTLA4, cytotoxic lymphocyte antigen 4; IL, interleukin; MMP, matrix metalloproteinases; PD-1, programmed cell death protein 1; TNF-α, tumor necrosis factor-α.

Fig. 4

Interactions among tumor-associated macrophages (TAMs) and other cellular components of the hepatocellular carcinoma (HCC) immune microenvironment during immunotherapy. Immunotherapies are rapidly becoming promising therapeutic approaches for patients with HCC. M2 TAMs largely contribute to the generation of an immunosuppressive environment by expressing multiple immune checkpoint molecules. Reprogramming TAMs from the M2 phenotype into the M1 phenotype might be a promising strategy for disrupting the immunotolerance-inducing mechanisms that occur during HCC immunotherapy. AKT, protein kinase B (PKB); CXCR, CXC chemokine receptor; CSF1, colony stimulating factor-1; CSF1R, CSF1 receptor; CT, cryptotanshinone; CTLA-4, cytotoxic lymphocyte antigen 4; ER, endoplasmic reticulum; HDACi, HDAC inhibitor; HLA-DR, human leukocyte antigen-antigen D related; IRF, interferon regulatory factor; mAb, monoclonal antibodies; LipC6, nanoliposome-loaded C6-ceremide; Lmdd-MPFG, Listeria monocytogenes-based tumor vaccine; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor kappa B; OPN, osteopontin; PD-1, programmed cell death protein 1; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homologue deleted on chromosome 10; SALL4, Sal-like protein-4; STAT3, signal transducer and activator of transcription 3; TIM, tumor-infiltrating macrophage; TLR, Toll-like receptor; TREM-1, triggering receptor expressed on myeloid cells-1; TRAIL, tumor necrosis factor (TNF)-related apoptosis-inducing ligand.