. 2021 May 13;67:103375. doi: 10.1016/j.ebiom.2021.103375

Table 2.

Targeting TAMs in CCA treatment.

Type of treatment	Target	Agent	Mechanisms	Experimental models	Major effects	References
TAMs Ablation	Macrophage depletion	Lipclod	Macrophages depletion	Xenograft model of human CCA cell lines, TAA-induced rat CCA model	Decrease CD68⁺ macrophages, reduced expression of Wnt7b and human pro-proliferation genes (BIRC5, CCND2, and CCNE), increased expression of apoptosis gene BAX1, increased apoptosis, less tumor burden	[53]
	CSFR1 inhibition	W2580 or AZD7507	Preventing macrophages recruitment and activation	Xenograft model of human CCA cell lines, TAA-induced rat CCA model	Decreased CD68⁺ and CD163⁺ macrophage, downregulation of Wnt7b, CTNNB1, cell cycle related genes (Ccnd1, Ctgf, Hedgehog receptors Ptch1 and Smo), progenitor phenotype genes (Jag1 and Klf5), reduced tumor load	[53]
	Anti-MCP-1 antibody	2H5	Preventing macrophages recruitment and activation	SNU-1079-generated human CCA cell xenografts	Reduced F4/80⁺ and CD206⁺ macrophages, significantly smaller tumors	[30]
	TWEAK/Fn14/NF-kB pathway	Fn14 knockout	Reduction of MCP-1 expression	TAA-treated mice	Reduced PanCK⁺ tumor epithelia cells and F4/80⁺ and CD206⁺ macrophages
TAMs repolarization	Macrophage stimulation	Pyroptotic CCA cells supernatants induced by MTX–TMPs	Activate macrophages to release proinflammatory factors	Activate macrophages to release proinflammatory factors	Production of various cytokines (IL-6, CCL2, CCL3 and CCL20) and neutrophil attractants (CXCL1, CXCL5 and TNF)	[106]
TAMs repolarization	Macrophage stimulation	Pyroptotic CCA cells supernatants induced by MTX–TMPs	Activate macrophages to release proinflammatory factors	CCA patients’ biliary drainage analysis	Upregulated production of CCL2, CCL3, CXCL1, CXCL5, IL-1β and IL-6	[106]
G-MDSCs and TAMs inhibition combined with anti-PD-1 therapy	G-MDSCs inhibition	Clone 1A8 or GW3965	Elimination immunosuppressive G-MDSCs	YAP-driven mouse CCA model	Reduced G-MDSCs and TAMs in the tumor site, increased CD8⁺ T cell infiltration and activation, significantly lessen tumor burden, prolonged the survival of mice bearing SB tumors	[80]
	Anti-CSF1R	AFS98	Preventing macrophages recruitment and activation
	Anti-PD-1 antibodies	G4	Promote anti-tumor immunity of CTLs
CD40 agonist and anti-PD-1 therapy	Agonistic anti-CD40	Clone FGK4.5	Induction of effective anti-tumor immune responses	Subcutaneous and intrahepatic tumor injection model, AKT 250 and YAP-driven mouse CCA model	Reduced of tumor growth and improved survival, increased CD4⁺, CD8⁺ and NK cell infiltration, enhanced response to chemotherapy	[86]
	Anti-PD-1 antibodies	Clone 29F.1A12	Promote anti-tumor immunity of CTLs
	Cytotoxic agents	Gemcitabine and Cisplatin	Cell cycle inhibition and DNA replication inhibition
CD47-SIRPα blockage	Anti-CD47 antibodies Anti-SIRPα	B6H12.2 SE5A5	Enhance macrophage phagocytosis	Transplenic intrahepatic metastasis mouse model	Reduced cancer colonization, increased phagocytic indices of resting, M1, M2, and TAM-like MDMs	[88]