Table 1.

Summary of studies evaluating the role of TANs in HCC pathogenesis.

Study (year)	Study Subjects	Primary Outcome	Secondary Outcome
He et al. [45] (2015)	Human/Animal	Infiltration of neutrophils is markedly higher in peritumoral tissue than in the actual tumor site	TNF-α and GM-CSF increase PD-L1 expression on neutrophils in the TME
He et al. [46] (2016)	Human	HGF production by neutrophils is TME mediated	GM-CSF is required for tumor neutrophil activation and HGF production
Cheng et al. [48] (2018)	Human	CAFs regulate the survival, activation, and function of neutrophils within HCC through an IL6–STAT3–PDL1 signaling cascade	IL6 induces PDL1+ neutrophils via the JAK-STAT3 pathway, impairing T-cell function through PD1/PDL1 signaling
Song et al. [49] (2021)	Human/Animal	CLCF1/CXCL6/TGF-β axis upregulates the recruitment of “N2” TANs in HCC	Levels of CLCF1−CXCL6/TGF-β axis are correlated with the number of intratumoral “N2” TANs and HCC prognosis
Zhou et al. [50] (2019)	Human/Animal	TANs secrete BMP2, TGF-β2 and trigger miR-301b-3p expression in HCC cells, suppressing gene expression of LSAMP, CYLD and increasing HCC stemness	Increased TANs correlated with elevated miR-301b-3p, decreased LSAMP and CYLD expression, higher nuclear p65 accumulation and CXCL5 expression
Peng et al. [51] (2020)	Human	Monocyte derived CXCL2 and CXCL8 regulate the recruitment of neutrophils sustaining their accumulation and survival in the TME	Levels of PFKFB3, CXCL2/CXCL8 production in monocytes and infiltration of OSM-producing neutrophils are positively correlated in HCC
Van der Windt et al. [52] (2018)	Human/Animal	Neutrophils infiltrate murine NASH livers and undergo NET formation. NET inhibition reduces monocyte infiltration, inflammation and progression of NASH to HCC	Commonly elevated free fatty acids stimulate NET formation in vitro
Li et al. [57] (2015)	Human	Activation of ERK1/2, p38, and NF-κB is required for autophagy induction in tumor neutrophils	Increased neutrophil autophagy contributes to the mitochondrial stabilization-mediated cell survival and promotes metastasis
Calvente et al. [61] (2019)	Animal	Neutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via miR-223	Neutrophils mediate the silencing of NLRP3 in proinflammatory macrophages via miR-223 and induce their alternative activation into a restorative phenotype after the cessation of injury

HCC: hepatocellular carcinoma; TAN: tumor-associated neutrophil; TNF: tumor necrosis factor; GM-CSF: granulocyte–macrophage colony-stimulating factor; PD-L1: programmed death ligand-1; TME: tumor microenvironment; ERK: extracellular signal-regulated kinase; NF: nuclear factor; HGF: hepatocyte growth factor; NET: neutrophil extracellular trap; NASH: nonalcoholic steatohepatitis; CAF: cancer-associated fibroblast; STAT: signal transducer and activator of transcription; IL: interleukin; JAK: janus kinase; LSAMP: limbic system-associated membrane protein; CYLD: CYLD lysine 63 deubiquitinase; NLRP3: NLR family pyrin domain containing 3; miR: microRNA; CXCL: chemokine C-X-C motif ligand; PFKFB: phosphofructo-2-kinase/fructose-2,6-biphosphatase; OSM: oncostatin-M; TGF-β: transforming growth factor-β; CLCF: cardiotrophin like cytokine factor; BMP: bone morphogenetic protein.