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Qin et al. Hepatoma Res 2020;6:24 I http://dx.doi.org/10.20517/2394-5079.2020.04 Page 3 of 18

Figure 1. HCC microenvironment components and linkage. A variety of immune-related cells in the tumor microenvironment can promote
or inhibit the development of hepatocellular carcinoma through various mechanisms. HCC: hepatocellular carcinoma; VEGF: vascular
endothelial growth factor; NK: natural killer; DC: dendritic cell; PDGF: platelet-derived growth factor; TGF: transforming growth factor;
HGF: hepatocyte growth factor; EGF: epidermal growth factor; FGF: fibroblast growth factor; MPPs: matrix metalloproteinases; NO: nitric
oxide; TNF: tumor necrosis factor; NKT: natural killer T cells; ROS: reactive oxygen species

expression of FoxP3 Tregs and then blocks CD4 CD25 T cell expression, at least promoting the progression
−
+
+
[14]
of HCC .
The chemotactic migration and selective activation functions of TAMs are achieved by osteopontin expressed
by HCC cells through the CSF1-CSF1R pathway . Many studies indicate that TAMs release many important
[15]
cytokines, including TNF-α, IL-6, IL-1β, and IL-23 and that they promote the expansion of Th17 cells, which
protects against antitumor immunity by activating several markers [16,17] . In addition, TAMs are able to induce
[18]
angiogenesis by producing angiogenic factors and matrix metalloproteinases . Recently, more studies have
[19]
determined that autophagy plays a key role in the functional control and immunosuppression of TAMs .

Tumor-associated neutrophils
Similar to macrophages, tumor-associated neutrophils (TANs) have different effects on the biological
behavior of tumors due to different degrees of polarization . Recent evidence suggests that TANs can be
[20]
classified into N1 (suppress tumor development) and N2 (promote tumor development) phenotypes on
the basis of TGF-β expression [19,20] . Some cytokines such as type I interferons and TGF-β can modulate
[21]
the activity of TANs . Studies have confirmed that the impact of neutrophils on tumor development is
regulated by CD8 T cells .
+
[22]