Table 1.

Summary of selected targets of TAM inhibition in PDAC mouse models.

Pathway	Method	Effect	Refs.
Macrophage depletion	Administration of macrophage toxin GdCl3	Blocked acinar-to-ductal metaplasia and the formation of pancreatic intraepithelial neoplastic lesions.	[37,38]
	Administration of Trabectedin	Activated caspase-8-dependent apoptosis in TAMs, and resulted in the reactivation of tumor-infiltrating lymphocytes that promote tumor cell death.	[141,142]
	Administration of clodronate-liposomes	Reduced tumor formation and metastasis by enhancing T-cell infiltration. Also synergized with gemcitabine chemotherapy to elicit a potent anti-tumor response.	[23,39,137,140]
	Administration of Lurbinectedin (PM00183)	Activated caspase-dependent apoptosis in cells by inducing DNA damage.	[143]
	Inhibiting CSF1R	Decreased tumor-initiating cells, reduced immunosuppression, and improved chemotherapeutic responses.	[20]
		Reduced tumor burden due to increased tumor cell death and an enhanced T-cell immune response.	[145]
		Improved response to immune check-point blockade, resulting in tumor regression.	[146]
Macrophage recruitment	Inhibiting CCR2	Enhanced anti-tumor immunity, decreased tumor growth, and reduced metastasis.	[21]
		Decreased number of cancer stem cells in pancreatic tumors and improved response to chemotherapy.	[20]
		Suppressed radiation-induced neovascularization and enhanced the efficacy of radiotherapy.	[19]
Macrophage reprogramming (suppressing AAM polarization)	Inhibiting PI3Kγ	Inhibited tumor cell invasion, metastasis, and desmoplasia.	[86,151]
		Slowed tumor development, impeded late-stage tumor growth and improved responsiveness to chemotherapy.	[152,153]
	Inhibiting CD11b	Reduced expression levels of immunosuppressive genes in TAMs, and enhanced T-cell immunity.	[166]
	Inhibiting IRF4	Depleted pancreatic lesions of AAMs and generated an inflammatory and immune-responsive environment.	[177]
	Inhibiting Mstr1	Decreased tumor size, suppressed alternative macrophage polarization, and enhanced T cell infiltration.	[208]
	Administration of IL27	Inhibited M2 macrophages polarization, dampened the proliferation, migration, and metastasis of pancreatic cancer cells, and enhanced the efficacy of gemcitabine.	[209]
	Inhibition of TIE2	Reduced tumor angiogenesis and presence of alternatively-activated macrophages at the invasive tumor front.	[180]
Macrophage reprogramming (stimulating CAM polarization)	Inhibiting RIP1	Reprogrammed TAMs towards an MHCIIhiTNFα+IFNγ+ immunogenic phenotype, and enhanced cytotoxic T-cell activation.	[155]
	Activating CD40	Improved infiltration of activated macrophages into tumors and depletion of tumor stroma. When combined with chemotherapy, anti-CD40 enhanced TAM activation and the clonal expansion of T-cells that resulted in tumor remission.	[158,159]
		Increased intratumoral accumulation and longevity of TCR-engineered T-cells that promote tumor cell apoptosis.	[160]
		When combined with a T-cell-inducing vaccine and anti-PD1 immune check-point blockade, anti-CD40 reprogrammed macrophages improved T-cell priming and activation.	[161]
	Blocking CD47	Improved macrophage-dependent phagocytosis of cancer cells, reprogrammed TAMs towards a pro-inflammatory tumoricidal endotype, and increased the number of intratumoral CD8 T-cells.	[140,171]