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Table 2 The potential targets and pathways that regulate HCC-TAMs phenotypic transition

From: Potential therapeutic targets in the tumor microenvironment of hepatocellular carcinoma: reversing the protumor effect of tumor-associated macrophages

Target

Pathway

Cell line or HCC model

Pro-tumor Results

RIPK3 and FAO

ROS-caspase1-PPAR pathway

Murine H22 cells and C57BL/6 WT mice injected with diethylnitrosamine as HCC model

The RIPK3-FAO-ROS-caspase1-PPAR signaling axis is responsible for increased M2-TAM infiltration, which promotes HCC tumorigenesis [106].

LINC00662

WNT3A-Wnt/b-catenin signaling

HCCLM3, MHCC97H, Huh7, SK-HEP-1, and Hepa1–6 HCC cells

By upregulating WNT3A expression, LINC00662 activates the Wnt/b-catenin pathway and then induces M2 macrophage polarization, contributing to HCC tumorigenesis and invasion and repressing HCC cell apoptosis [107, 108].

IL-25

/

Human HCC cell lines MHCC97L and HepG2 cells; Murine HCC cell lines H22, and Hepa1–6; and BALB/c nude mice with the portal venous injection macrophages as HCC model.

IL-25 facilitates M2 TAM (CD206/CD68) infiltration, promotes secretion of the chemokine CXCL-10, and then induces HCC progression through the EMT pathway [109].

CAF-induced endosialin

Interaction with CD68 and regulate GAS6 expression in CAF

Huh7 cell HFL-1 cells

In CAFs, via an interaction with CD68, endosialin promotes the expression of GSA6, which results in increased M2 macrophages recruitment and HCC progression [110].

HCC-derived HMGB1

ROS-TLR2-NOX2-autophagy axis

Mouse hepatoma cell line ML-14a cells and murine in a situ hepatoma model

Hepatoma-derived HMGB1 stimulates ROS via the TLR2/NOX2 axis, thereby inducing M2 macrophage polarization and subsequently supporting HCC growth [111].

Nogo-B

Nogo-B-Yap/Taz pathway

Murine HCC cell lines Hepa1–6 cells and H22 cells, macrophage cell line RAW 264.7 cells

Elevated Nogo-B expression facilitates M2 TAM polarization and promotes HCC tumor growth in vivo by inducing Yap/Taz signaling [112].