TABLE 2.

Preclinical agents and clinical trials targeting TAMs for HCC treatment

Treatment strategy	Drug name	Combinational therapy	Cancer type	Results	Clinical trial number or Reference
Inhibiting the transition of monocytes to M2 TAMs
Blocking CSF‐1/CSF1R	Cabiralizumab	Anti‐PD1‐mAb: Nivolumab	HCC	Clinical trial for HCC patients(ongoing)	NCT04050462
	Chiauranib	N/A	HCC	Clinical trial for HCC patients	NCT03245190
	GW2580 or AZD7507	N/A	iCCA	Inhibit iCCA growth in xenografts model	[151]
	Anti‐CSF1R:AFS98	Anti‐Ly6G:1A8 and anti‐PD‐1: G4	iCCA	Potentiate anti‐PD‐1 therapy and attenuate iCCA progression	[145]
	SNDX‐6532	Durvalumab	iCCA	Clinical trial for iCCA patients(ongoing)	NCT04301778
CCL2/CCR5 antagonist	BMS‐813160	Anti‐PD1‐mAb: Nivolumab	HCC	Clinical trial for HCC patients(ongoing)	NCT04123379
	Cenicriviroc	N/A	HCC	Reverse liver damage and steatosis	[152]
CCR2 antagonist	747	Low‐dose sorafenib	HCC	Anti‐tumor and enhance the efficacy of sorafenib	[154]
	RDC018	N/A	HCC	Inhibit HCC growth and metastasis	[153]
CCL2 antibody	2H5	N/A	iCCA	Downregulate macrophage accumulation and suppress tumor growth	[114]
C/EBPα saRNA	MTL‐CEBPA	Sorafenib	HCC	Clinical trial for HCC patients (ongoing)	NCT02716012/[155]
	MTL‐CEBPA	Pembrolizumab	HCC/iCCA	Clinical trial for solid tumor patients (ongoing)	NCT04105335
CCL5 blockade	aPKCɩ‐siRNA	Gemcitabine	iCCA	Inhibited TAM infiltration and iCCA progression	[156]
Remodeling M2 TAMs to M1 TAMs
Tyrosine kinase inhibitors	Sorafenib	N/A	HCC	Inhibit tumor growth and improve survival	[165]
Pan‐PI3K inhibitor	SF1126	Anti‐PD1‐mAb: Nivolumab	HCC	Clinical trial for HCC patients	NCT03059147
PI3Kγ inhibitor	TG100‐115	Sorafenib	HCC	Higher levels of antitumor efficiency	[170]
	GSK2636771	N/A	iCCA	MATCH Screening Trial for solid tumor patients(ongoing)	NCT02465060
RIPK3 inhibitor	GSK872	N/A	HCC	Dampened HCC tumorigenesis	[18]
Natural compound	Baicalin	N/A	HCC	Suppress tumor progression	[108]
CSF‐1R inhibitor	PLX3397	Anti‐PD‐L1	HCC	Suppress tumor progression	[167]
C‐Met and EGFR inhibitor	Norcantharidin	N/A	HCC	Suppress tumor progression	[169]
Agonistic anti‐CD40	Clone FGK4.5	Anti‐PD‐1 antibodies: Clone 29F.1A12	iCCA	Increase the infiltration of immune cells and inhibit iCCA growth	[171]
Tie2 inhibitor	Regorafenib	N/A	HCC	Clinical trial for HCC patients	NCT04476329
	Regorafenib	Nivolumab	HCC	Clinical trial for HCC patients(ongoing)	NCT04170556
	Regorafenib	PD‐1 inhibitor	HCC	Clinical trial for HCC patients(ongoing)	NCT05048017
	Regorafenib	N/A	HCC	Improves overall survival in HCC patients with sorafenib treatment	[176]
TLR7 agonist	RO7119929	Tocilizumab	HCC/iCCA	Clinical trial for HCC/iCCA patients(ongoing)	NCT04338685
	GS‐9620	Anti‐SIGLEC‐3 mAb	HCC	Reducing the risk of HCC in chronic hepatitis patients	[172]
Eliminating specific pre‐tumoral tissue‐resident macrophages in liver cancer
Microtubule polymerization inhibitor	CA1P	Sorafenib	HCC	Suppress tumor growth and enhance the effect of PD‐1 sorafenib	[157]
Macrophage depletion drug	Zoledronic acid	Sorafenib	HCC	Suppress tumor growth and enhance the effect of PD‐1 sorafenib	[158]
	Lipclod	N/A	iCCA	Deplete phagocytic macrophages and inhibit iCCA growth	[151]
	Zoledronic acid	Sorafenib	HCC	Clinical trial for HCC patients(ongoing)	NCT01259193
Tyrosine kinase inhibitors	Lenvatinib	Anti‐mouse PD‐1 antibody	HCC	Suppress tumor growth and enhance the effect of PD‐1 antibody	[159]
Antioxidant agent	CeO2NPs	N/A	HCC	Eliminating existent TAMs and Suppress tumor progression	[160]
Blocking the communication between M2 TAMs and liver cancer cells
A2A antagonist	SCH58261	Anti‐GM‐CSF antibodies	HCC	Eliminating existent TAMs and Suppress tumor progression	[14]
CD47‐SIRPα blocking	Anti‐human‐SIRPα	N/A	HCC	Clinical trial for HCC patients	NCT02868255
	Anti‐CD47‐Ab	TACE or Tocilizumab	HCC	Suppress tumor growth and enhance the effect of TACE	[184]
	Anti‐CD47‐Ab	Doxorubicin	HCC	Suppress tumor growth and enhance the effect of doxorubicin	[187]
	CD47mAb400	N/A	HCC	Suppress tumor progression	[188]
	Anti‐CD47‐Ab	B6H12.2	iCCA	Promotes macrophage phagocytosis and suppress iCCA growth	[186]
CAR‐M
CAR macrophages	CT‐0508	N/A	HCC	Clinical trial for Her2 overexpressing patients(ongoing)	NCT04660929

Abbreviations: A2A, adenosine A2a receptor; CAR‐M, chimeric antigen receptor macrophage; CCL2, C‐C motif chemokine ligand 2; CCL5, C‐C motif chemokine ligand 5; CCR2, C‐C motif chemokine receptor 2; CCR5, C‐C motif chemokine receptor 5; C/EBPα, CCAAT/enhancer‐binding protein alpha; CSF1, colony‐stimulating factor‐1; CSF1R, colony‐stimulating factor 1 receptor; EGFR, epidermal growth factor receptor; HCC, hepatocellular carcinoma; iCCA, intrahepatic cholangiocarcinoma; IL6, interleukin 6; PD1, programmed cell death protein 1; PI3Kγ, Phosphoinositide 3‐kinase gamma; RIPK3, receptor‐interacting protein kinase 3; saRNA, small activating RNA; SIGLEC‐3, sialic acid binding Ig like lectin 3; SIRPα, signal regulatory protein alpha; TACE, transcatheter arterial chemoembolization; TAMs, tumor‐associated macrophages; TLR7, toll‐like receptor 7.