Table 1.

The verified regulating methods and targets that could repolarize TAMs to anti-HCC phenotypes

Phenotypic Change	Regulating method	HCC model	Pathway	Effects
M2 to M1	miR-99b transfection	Hepa1–6 cells injected mice	κB-Ras2 and/or mTOR; a positive feedback regulation loop of NF-κB	miR-99b amplifies M1 macrophage function, resulting in increased phagocytosis and antigen presentation, which impedes the growth of murine HCC [79]
M0 to M1; M2 to M1	a nanoliposome-loaded C6-ceremide (LipC6) injection	C57BL/6 mice received injections of oncogenic hepatocytes	ROS signaling	LipC6 enhances M1 cytokine production while inhibiting M2 cytokine production, thereby reversing immune suppression, and increasing CD8+ T cells activity [80]
M0 to M1; M2 to M1	Listeria-based HCC vaccine, Lmdd-MPFG combined with PD-1 blockade	Hepa1–6/MPFG tumor-bearing mice	NF-κB pathway through the TLR2 and MyD88 pathway	Lmdd-MPFG induces an increase in T cells number in the HCC TME and promotes the production of cytokines, such as IFN-γ [81].
M1-type activated; M2-type decreased	dual anti-PD-1/VEGFR-2 therapy	HCA-1 in C3H mice and RIL-175 in C57Bl/6 mice.	selectively upregulated pathways associated with myeloid cells and B cells	Combination PD-1and VEGFR-2 blockade therapy shifts the TAM ratios of F4/80+ CD80+ and/or CD86+ M1 TAMs to F4/80+CD206+ M2 TAMs, which also regulates the infiltration of other immune cells and reprograms the TME to an antitumor state in HCC [82].
M0 to M1	upregulate RIG-I expression	H22 liver cancer cells inoculated C57BL/6 mice	RIG-I/ MAVS/TRAF2/NF-κB pathway	RIGI-induced M1 macrophages promoted apoptosis and death in HCC cells in vivo and in vitro [83].
M0 to M1	upregulated SIRT1	HepG2 and RAW 264.7, HL-60 macrophages	NF-κB pathway	SIRT1 overexpression enhances M1-like macrophage infiltration in HCC while inhibiting HCC cell growth, migration, and invasion [84].
M2 to M1	upregulate IL-37 expression	HepG2 and Huh-7 cells injected BALB/c nude mice and HCC-conditioned TAMs	IL-6/STAT3 signaling.	IL-37 inhibits M2 polarization of TAMs and then suppresses HCC cell activities, including growth, migration, and invasion. In vivo, upregulated IL-37 expression in HCC-conditioned TAMs delays tumor growth [85].
M2 to M1	miR-98 mimics	HepG2 and SMMC7721 cells incubated with the culture medium of TAMs	targeting IL-10	miR-98 reverses M2 polarization in HCC and inhibits the TAM-mediated promotion of invasion, migration, and epithelial-mesenchymal transition in HCC [86, 87].