Role of tumor-associated macrophages in common digestive system malignant tumors

Table 1 Tumor-associated macrophages can promote the development of tumors

Diseases	Factors	Functions	Mechanism	Ref.
EC	GDF-15 derived from TAMs	Promoting progression of ESCC	Activating TGF-β type II receptor	[44]
GC	TAMs	Promoting peritoneal dissemination of GC	Secreting IL-6	[53]
	TAMs	Promoting progression in GC	Polarizing to the M2 phenotype	[54]
	TAMs	Supporting peritoneal metastasis	Producing EGF and VEGF	[55]
	TNF-alpha and IL-6 secreted by TAMs	Promoting proliferation of GC cells	Activating the NF-κB and STAT3 signaling pathway to regulate PD-L1 expression	[56]
	TGFβ2 secreted by TAMs	Promoting the invasion of GC cells	Regulating Kindlin-2 through NF-κB	[57]
	CCL5 secreted by TAMs	Promoting the proliferation, invasion and metastasis of GC cells	Stat3 signaling pathway	[58]
	TAMs	Influencing omental milky spots and lymph nodes micrometastasis	COX-2/PGE-2/TGF-β/VEGF signal pathways	[59]
	TAMs	Promoting epigenetic silencing of tumor suppressor gelsolin, and silence GSN	Upregulation of DNMT1 by CCL5/CCR5/STAT3 signaling	[60]
	TAMs	Inducing invasion and poor prognosis in GC	Promoting MMP9 expression	[63]
	MMP-9 secreted by TAMs	Suppressing distant metastasis in GC	PI3K/AKT/Snail dependent pathway	[64]
	Exosomal miR-487a derived from TAMs	Promoting the proliferation and tumorigenesis in GC	-	[65]
	M2 macrophage-derived exosomes	Remodeling the cytoskeleton-supporting migration in recipient GC cells	Mediating an intercellular transfer of ApoE-activating PI3K-Akt signaling pathway	[66]
CRC	TAMs	Potentiating the angiogenic capacity of the TME	Oxidative stress-dependent manner	[91]
	Metabolic reprogramming in TAMs	Building a bridge between metabolic dysfunction and the onset and progression of CRC	Inflammatory pathways	[92]
	M2 macrophage-derived exosomes	Promoting CRC cells’ migration and invasion	MiR-21-5p and miR-155-5p	[93]
	Exosomal miR-183-5p Shuttled by M2 TAMs	Promoting the development of colon cancer	THEM4 mediated PI3K/AKT and NF-κB pathways	[94]
	MMP1 derived from TAMs	Facilitating colon cancer cell proliferation	Accelerating cell cycle transition from G0/G1 to S and G2/M phase	[95]
	M2 TAMs	Inducing colon cancer cell invasion	MMP-9	[96]
	Cathelicidin secreted by TAMs	Promoting the growth of CRC	Recruiting inflammatory cells	[97]
PC	Intraperitoneal TAMs	Promoting peritoneal dissemination and chemoresistance	Inducing EMT	[123]
	M2 TAMs	Promoting EMT	TLR4/IL-10 signaling	[124]
	TAMs	Promoting progression and the Warburg effect	CCL18/NF-Kb/VCAM-1 pathway	[125]
	CCL20 secreted by M2 TAMs	Promoting the migration, epithelial-mesenchymal transition, and invasion of pancreatic cancer cells	-	[126]
	TAMs	Orchestrating functions PDA-infiltrating T cells	Odulating PDA-infiltrating T cells epigenetic profile towards a pro-tumoral phenotype	[42]
LC	TAMs	Promoting LCSLC self-renewal capability and carcinogenicity	M2 polarization	[151]
	TAMs	Promoting EMT of Hep3B hepatoma cells	TLR4	[153]
	IL-6 secreted by TAMs	Promoting expansion of these CSCs and tumorigenesis	STAT3 signaling	[154]

Tumor-associated macrophages (TAMs) contribute to the development of esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer and liver cancer. The effective factors are TAMs and their derivants or secretions. The function indicates that how these factors exert influence on tumor progression, concerning proliferation, invasion, metastasis, migration and so on. In addition, the mechanism indicates the corresponding signaling pathways or regulatory intermediates, through which TAMs and their derivants promote or suppress development of the cancers. The last column indicates the corresponding reference of the entry. EC: Esophageal cancer; GC: Gastric cancer; CRC: Colorectal cancer; PC: Pancreatic cancer; LC: Liver cancer; GDF-15: Growth/differentiation factor-15; TAM: Tumor-associated macrophages; ESCC: Esophageal squamous cell carcinoma; TGF-β: Transforming growth factor-β; IL: Interleukin; EGF: Epidermal growth factor; VEGF: Vascular endothelial growth factor; TNF-α: Tumor necrosis factor-α; NF-kB: Nuclear factor kB; STAT3: Signal transducers and activator of transcription 3; PD-L1: Programmed Cell Death Ligand 1; PGE-2: Prostaglandin E2; PI3K: Phosphoinositide 3-kinase; MMP9: Matrix metalloproteinases 9; CCL5: CC ligand 5; TLR4: Toll like receptor 4; LCSLC: Liver cancer stem-like cell; CSC: Cancer stem cell.

Table 2 Tumor-associated macrophages act as potential therapeutic targets for tumors

Diseases	Factors	Types	Targets	Functions	Mechanism	Ref.
EC	MiR-498	MiRNA	Inhibiting autophagy and M2-like polarization of TAMs in esophageal cancer	-	Inhibiting MDM2-mediated ATF3 degradation	[45]
	MiR-155	MiRNA	Regulating TAMs FGF2 expression	Suppressing EC cell proliferation, migration, invasion and inhibiting vasculature formation	-	[46]
	EC-Derived Extracellular Vesicle miR-21-5p	MiRNA	Disorganizing macrophages polarization	Contributing to EMT of ESCC cells via TGF-β/Smad2 signaling	PTEN/AKT/STAT6 pathway	[47]
	PTEN	Protein	Inducing M2 TAMs polarization	Enhancing the malignant behavior of TECs, promoting ESCC angiogenesis	Activating the PI3K/AKT signaling pathway	[48]
	NCAM- and FGF-2-mediated FGFR1 signaling	Signaling	Regulating the survival and migration of TAMs and cancer cells	-	NCAM knockdown via a suppression of PI3K-Akt and FGFR1 signaling, and rhFGF-2 -through FGFR1 signaling	[49]
	HR-HPV; HPV16 infection	Virus	Promoting M2 macrophages phenotype	Promoting the invasion and metastasis of esophageal squamous cell carcinoma	-	[50]
GC	STING	Gene	Promoting TAMs polarizing into pro-inflammatory subtype	Inducing apoptosis of GC cells	IL6R-JAK-L24pathway	[67]
	LINC00665	LncRNA	Activating Wnt1 and mediating TAMs M2 polarization	-	Interacting with BTB domain and BACH1	[68]
	CALM2	Protein	Polarizing TAMs	Facilitating angiogenesis and metastasis of GC	STAT3/HIF-1A/VEGF-A	[69]
	MENK	Protein	Skewing macrophages toward M2 phenotype from M1 phenotype	Inducing cells apoptosis	OGFr/PI3K/AKT/Mtor signaling pathway	[70]
	ELK4	Transcription factor	Promoting M2 polarization	Promoting the development of GC	Reducing the PJA2-dependent inhibition of KSR1 by transcriptional activation of KDM5A	[71]
	IL-6	Cytokine	Polarizing the Mφs	Promoting tumor invasion	IL-6/STAT3/IRF4 signaling pathway	[72]
	GC-MSCs	Cell	Promoting M2 polarization	Promoting metastasis and EMT in GC	Secreting IL-6 and IL-8	[73]
	Vasoactive intestinal peptide	Protein	Repressing activation of TAMs	-	Regulating TNFα, IL-6, IL-12 and Inos	[74]
	Lipid droplet-dependent fatty acid	Fatty acid	Controlling the immune suppressive phenotype of TAMs	-	-	[75]
	MiR-151-3p derived from GC exosomes	Exosome	Inducing M2-phenotype polarization	Promoting tumor growth	-	[76]
	IL-33-mediated mast cell	Cell	Mobilizing macrophages	Promoting GC	-	[77]
CRC	PKN2	Protein	Inhibiting M2 phenotype polarization	-	DUSP6-Erk1/2 pathway	[98]
	AQP9	Protein	Stimulating M2-like polarization	Promoting colon cancer progression	Transporting lactate	[99]
	PKCα	Tumor suppressor	Promoting M1 macrophages polarization	-	MKK3/6-P38 signaling pathway	[100]
	MK2	Protein	Promoting polarization of protumorigenic TAMs	-	-	[101]
	MiR-195-5p/NOTCH2-mediated EMT	-	Affecting M2-like TAMs polarization	-	Modulating IL-4 secretion	[102]
	CRC cell-derived exosomal miR-934	Exosome	Inducing M2 macrophages polarization	-	Downregulating PTEN expression and activate the PI3K/AKT signaling pathway	[103]
	Stimulator of STING pathway	Signaling pathway	Activating reprogramed TAMs toward the M1 phenotype	-	-	[104]
	Colon cancer cell	Cell	Promoting M2 polarization of TAMs	-	Secreting EGF; EGFR/PI3K/AKT/Mtor pathway	[105]
	CXCL10 and CXCL11	Chemokine	Inducing the infiltration of TAMs	Leading to the poor prognosis of CRC	-	[106]
	β-1, 6-glucan	Organic compound	Reseting TAMs from M2-like to M1-like phenotype	Inhibiting the viability of colon cancer cells	Increasing the phosphorylation of Akt/NF-κB and MAPK	[107]
	H. pylori infection	Becteria	Reducing the infiltration of M2-like TAMs	-	Downregulating TNF-α, IL-1β, IL-6 and IL-23	[108]
PC	Autophagy-dependent ferroptosis	-	Driving TAMs polarization	-	Releasing and uptaking of oncogenic KRAS protein	[127]
	RIP1	Kinase	Reprogramming TAMs	-	STAT1-dependent manner	[40]
	Deletion of CAF-HIF2	Protein	Decreasing the intratumoral recruitment of immunosuppressive M2 macrophages	-	-	[128]
	ADH-503	Small-molecule agonist	Leading to the repolarization of TAMs	-	Partial activation of CD11b	[129]
	NLRP3	Inflammasome	Regulating TAMs polarization	Enhancing lung metastasis of PDAC	-	[130]
	IL-27	Cytokine	Targeting M2 TAMs	Dampening the proliferation, migration and metastasis of PC cells	-	[131]
	IFN-γ	Chemokines	Preventing trafficking of TAMs	Improving the efficacy of PD1 blockade therapy in PC	Blocking the CXCL8-CXCR2 axis	[132]
	PC-derived exosomal FGD5-AS1	Exosome	Stimulating M2 macrophages polarization	Promoting proliferation and migration of PC cell	Activating STAT3/NF-κB pathway	[133]
	PDAC-derived Sev-EZR	Exosome	Modulating TAMs polarization	Promoting PDAC metastasis	-	[134]
	CUX1	Transcription factor	Mediating M1 polarization	Inhibiting angiogenesis and tumor progression	Downregulating several NF-κB -regulated chemokines	[135]
	Tryptophan-derived microbial metabolite	Metabolite	Activating the aryl hydrocarbon receptor in TAMs	Suppressing anti-tumor immunity	-	[136]
	Nrf2	Transcription factor	Stimulating M2 macrophages polarization	Promoting EMT	Activating cancer cell-derived lactate	[137]
	Lactic acid	Organic compound	Redistributing M2TAMs subsets	Upregulating PDL1 to assist tumor immune escape	HIF1α signaling pathway	[138]
	Activation of DRD4 by DA	Protein	Suppressing the tumor-promoting inflammation of TAMs	-	Decreasing Camp; inhibit the activation of PKA/p38 signal pathway	[139]
	PDA cells	Cell	Reprogramming M1-like macrophages	-	GARP-dependent and DNA methylation-mediated mechanism	[140]
LC	Ndrg2	Gene	Influencing TAMs polarization	-	NF-κB pathway	[155]
	TREM1knockdown	Gene	Shifting M2 macrophages towards a M1 phenotype	-	Inhibiting PI3K/AKT/Mtor activation	[156]
	MiR-99b	MiRNA	Promoting M1 while suppressing M2 macrophages polarization	-	Targeting κB -Ras2 and/or mTOR	[157]
	MAGL	Kinase	Promoting the transcription and secretion of inflammatory factors in TAMs	-	-	[158]
	-	-	Blocking triggering receptor expressed on myeloid cells-1-positive TAMs	Reversing immunosuppression and anti-PD-L1 resistance in LC	-	[159]
	Regorafenib	Multikinase inhibitors	Reversing M2 polarization	-	Suppressing p38 kinase phosphorylation and downregulating Creb1/Klf4 activity in BMDMs	[160]
	ZIP9	Protein	Promoting M2 macrophages polarization	-	Enhancing phosphorylated STAT6	[161]
	Phosphoinositide-related signaling pathway	Signaling pathway	Reprogramming TAMs	-	Enhancing activation of the PI3K/Akt pathway	[162]
	Inhibite VEGF signaling pathway	Signaling pathway	Attenuating TAMs activity in liver cancer	-	-	[163]
	SALL4-mediated upregulation of exosomal miR-146a-5p	Exosome	Leading to M2-polarized TAMs	-	Activating NF-κB signaling and inducing pro-inflammatory factors	[43]
	Activated HSCs	Cell	Converting macrophages to TAMs	-	-	[164]

In esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer and liver cancer, there are multifarious approaches to regulate tumor-associated macrophages (TAMs), the effective factors of which, and corresponding types, are presented in the second and third column. The targets indicate which behaviors of TAMs that are modulated. In addition, the functions, mechanism and reference section are similar as Table 1. EC: Esophageal cancer; GC: Gastric cancer; CRC: Colorectal cancer; PC: Pancreatic cancer; LC: Liver cancer; TAM: Tumor-associated macrophages; PTEN: Phosphatase and tensin homolog; TEC: Tumor endothelial cells; STAT3: Signal transducers and activator of transcription 3; ESCC: Esophageal squamous cell carcinoma; NCAM: Neural cell adhesion molecule; FGF-2: Fibroblast growth factor 2; HPV: Human papillomavirus; VEGF: Vascular endothelial growth factor; STING: Stimulator of interferon genes; MSC: Mesenchymal stem cell; TNF-α: Tumor necrosis factor-α; IL: Interleukin; PI3K: Phosphoinositide 3-kinase; EGF: Epidermal growth factor; EGFR: Epidermal growth factor receptor; STAT1: Signal transducers and activator of transcription 1; IFN-γ: Interferon-γ; GARP: Glycoprotein A repetitions predominant; HIF-1α: Hypoxia-inducible factor-1α; PD-L1: Programmed Cell Death Ligand 1; EMT: Epithelial mesenchymal transition; mTOR: Mammalian target of rapamycin; HSC: Hematopoietic stem cell; OGFR: Opioid growth factor receptor; Nrf2: Nuclear factor erythroid 2-related factor 2.