Table 3.

The protumor mechanisms of neutrophils in different cancer models

Cancer type	Model	Influence factor	Effect	Anticancer mechanism	Reference
Colorectal cancer	Recombinase-activating gene-2-deficient (Rag2−/−) mice	Helicobacter pylori	Infection leads to the accumulation of neutrophils in the colon, ultimately promoting intestinal carcinogenesis.	During infectious conditions, TNF-α-driven accumulation of neutrophils in the colon results in the release of abundant NO, promoting intestinal carcinogenesis.	[54]
Colon cancer	Gpx4+/Δmye and Gpx4Δ/Δmye mice	ROS released by bone marrow cells	Myeloid cell-derived ROS induce epithelial mutagenesis.	Lack of Gpx4 in bone marrow cells leads to increased ROS production, while increased oxidative stress can induce tumor development.	[55]
Colorectal cancer	Human samples, dextran sodium sulfate induced colitis in mice, and acute mucosal injury in mice	Pro-inflammatory particles miR-23a and miR-155	Neutrophils induce the impairment of colon healing and genomic instability.	Neutrophil-derived miR-23a and miR-155 induce double-strand breaks, leading to the occurrence of cancer.	[56]
Lung adenocarcinoma	A549 (K-ras mutant) and K-ras WT 201 T cell lines and LSL-K-ras mice and cell lines	NE	NE derived from neutrophils promotes lung tumor growth.	NE degrades IRS1, leading to activation of PI3K, which ultimately promotes cancer proliferation.	[57]
Melanoma	Human samples and RAS driven tumor formation in zebrafish	PGE2	Neutrophils promote cancer cell proliferation and growth by releasing nutrient factor PGE2.	The PGE2 released by neutrophils induced by wound inflammation can promote the proliferation of pretumor cells.	[58]
Prostate cancer	Human samples, Ptenpc−/− mice, and PC3 human prostate cancer cell lines	APOE released by tumor cells	Tumor-induced aging (TREM2+) neutrophils persist in the tumor microenvironment and exert immunosuppressive effects.	The APOE released by tumor cells binds to TREM2 on neutrophils, inducing neutrophil aging. A series of cytokines secreted by TREM2+ neutrophils mediate immune suppression.	[59]
Prostate cancer	Human samples, male Il1ra−/− mice, and Pten−/− mouse embryonic fibroblasts (MEFs)	IL-1RA	Tumor-infiltrating neutrophils antagonize tumor cell aging.	IL-1RA secreted by neutrophils can antagonize aging.	[60]
Breast cancer	MDA-MB-231 cell line and T47D human breast cancer cell line	OSM	OSM secreted by neutrophils induces VEGF expression in breast cancer cells, promoting angiogenesis and invasion.	GM-CSF derived from breast cancer cells stimulates neutrophils to release OSM, and the latter induces VEGF expression by activating the JAK-STAT pathway after combining with tumor cells.	[61]
Colorectal cancer with liver metastasis	Human samples and intrasplenic injection of human colorectal cancer cells into mice	FGF2	Neutrophils induce metastatic angiogenesis by promoting the production of FGF2.	FGF2 can be produced directly by tumor-associated neutrophils or released by neutrophils secreting heparinase to degrade ECM.	[62]
Gastric cancer	Human gastric cancer cell lines BGC-823, MGC80–3, SGC-7901, and HGC-27	HMGB1	Exosomes derived from gastric cancer cells carrying HMGB1 induce neutrophil autophagy.	Gastric cancer cell-derived exosomes (HMGB1) induce neutrophil autophagy through the activation of the HMGB1/TLR4/NF-κB pathway, leading to the release of pro-tumor cell migration factors such as IL-1β and OSM.	[63]
Breast cancer	Murine D2.0R and human MCF-7 cell lines	NE and MMP-9	Under the induction of inflammation, NETs induce the recovery of dormant cancer cells.	NE and MMP-9 released by NETs sequentially cut laminin to produce integrin α3β1 activation epitopes.	[64]
Melanoma	Inject A375M, 1205 Lu, C8161.Cl9 or UACC 903 M cells into mice	IL-8	IL-8 secreted by melanoma promotes neutrophil recruitment and interaction with tumor cells.	β2 integrins on neutrophils and intercellular adhesion molecule-1 on tumor cells mediate their interactions.	[65]
Breast cancer, lung cancer, and colon cancer	Human samples and 4 T1, LLC, HT29, CT26 tumor-bearing mice	CXCR1 CXCR2	The barrier of NETs is beneficial for tumor cells to avoid immune toxicity damage mediated by CD8+ T cells and NK cells.	Tumor-derived CXCR1 and CXCR2 induce the formation of NETs, which increase the interception of circulating tumor cells.	[66]
Breast cancer	Spontaneous, experimental breast cancer metastasis in mice	Resident mesenchymal cells (MCs) in the lungs	Under the stimulation of lung-resident MC, neutrophils accumulate a large amount of lipids to provide energy for tumor cells.	MCs trigger lipid storage in neutrophils, which then transfer their stored lipids to disseminated tumor cells for survival by releasing vesicles.	[67]
Lymphoma, colon cancer, and lung cancer	EL4 lymphoma, and CT26 (colon cancer) and LLC tumor-bearing mice	MPO	Neutrophils limit antigen cross presentation of dendritic cells (DCs).	The MPO of neutrophils drives lipid peroxidation, and the subsequent transfer of this oxidized lipid from neutrophils to DC limits the antigen cross-presentation effect of the latter.	[68]
Lewis lung carcinoma, lymphoma, colon carcinoma, and sarcoma	GEM mice for LLC, CT26, and KPC, EL-4 tumor-bearing mice, and the EL4, LLC, CT26, and TC-1 F244 cell lines	FATP2 and PGE2	Neutrophils expressing FATP2 mediate immune suppression by inducing PGE2 synthesis.	The expression of FATP2 by neutrophils leads to an increase in the uptake of arachidonic acid, thus promoting the biosynthesis of PGE2 and ultimately exerting T cell inhibition.	[25]
Lymphoma, Lewis lung carcinoma, and colon carcinoma	Human samples and EL4, EG7, LLC, CT26, and MC-38 tumor-bearing mice	Ferroptosis and PGE2	Neutrophils undergoing ferroptosis induce tumor immunosuppression.	The number of neutrophils undergoing ferroptosis decrease, but lipid mediators such as PGE2 limit the activity of T cells.	[69]
Lewis lung carcinoma	PL and LLC tumor-bearing mice	ARG1	ARG1 limits the function of T cells by consuming arginine, and its expression is predominant in neutrophils.	Neutrophils actively transcribe ARG1 through the membrane-associated protein A2/TLR2/MYD88 axis, promoting the immunosuppressive effect of neutrophils.	[70]
Hepatocellular carcinoma	Human samples and H22 tumor-bearing mice	TNF-α, GM-SCF, and the PD-L1/PD-1 axis	PD-L1 expression on neutrophils negatively regulates adaptive immune T cells.	Tumor-derived cytokines such as TNF-α and GM-SCF help induce PD-L1 expression on neutrophils.	[71]
Hepatocellular carcinoma	Human samples	IL-6, PD-L1/PD-1 axis	CAFs promote immune suppression of cancer cells through the IL6-STAT3-PDL1 signaling pathway.	IL-6, secreted by HCC-derived CAF, induced the upregulation of PD-L1 expression in neutrophils through the JAK-STAT3 signaling pathway.	[72]
Gastric cancer	Human samples and the human BGC-823 cell line	HMGB1 and the PD-L1/PD-1 axis	Gastric cancer cells activate the immunosuppressive effect of neutrophils through the GM-CSF-PD-L1 pathway.	Tumor cell-derived vesicle transport (HMGB1) upregulates PD-L1 expression in neutrophils by activating the STAT3 pathway.	[73]
Melanoma, Lewis lung carcinoma, colon carcinoma, and mammary carcinoma	B16-F10, LLC, CT26, and 4 T1 tumor-bearing mice	Hypoxia and the PD-L1/PD-1 axis	Hypoxia selectively upregulates PD-L1 on neutrophils, affecting T cell antitumor activity.	Hypoxia-induced HIF-1α directly binds to the proximal HRE of PD-L1 and upregulates the expression of PD-L1 on neutrophils.	[74]
Burkitt lymphoma, breast cancer, colon adenocarcinoma, and renal carcinoma	Raji, SK-BR-3, DLD-1, LS-174 T, HT-29, HCT-116, Caki-1, RCC4, RCC10, and TK10 cell lines and SRG mice	CD47/SIRPα axis	Tumors impair the antitumor activity of neutrophils and macrophages through the CD47/SIRPα axis.	Tumors express the “don’t eat me” signal CD47, which when combined with the ligand SIRPα on macrophages and neutrophils causes tumors to evade immune injury.	[75]
Cervical cancer	TC-1 tumor-bearing mice	C5a, ROS and RNS	C5a induces neutrophil disruption of T cell activity.	C5a promotes the migration of neutrophils to tumors and the release of ROS and RNS from neutrophils to impair T cell activity.	[76]
Breast cancer	Metastatic C4 T1 mice	IL-10 and IL-12	Neutrophils induce macrophage polarization toward the M2 phenotype, promoting the formation of an immunosuppressive environment.	The production of IL-10 by neutrophils leads to a decrease in IL-12 production by macrophages, ultimately leading to polarization to the M2 phenotype.	[77]
Lung adenocarcinoma	Autochthonous GEM mice	Commensal Microbiota, γδ T cells and IL-17	The symbiotic microbiome induces γδ T cells and neutrophils to copromote tumor progression.	The microbiota stimulates the production of IL-1β and IL-23 by neutrophils, which induce the activation of lung-resident gamma-δ T cells. γδ T cells, in turn, produce IL-17 to induce neutrophil infiltration.	[78]