Roles of tumor associated neutrophils in the development of hepatocellular carcinoma and therapeutic implications.

Roles of tumor associated neutrophils in the development of hepatocellular carcinoma and therapeutic implications - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Search Log in Primary site navigation Search Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Discov Oncol . 2026 Apr 21;17:841. doi: 10.1007/s12672-026-05046-5 Roles of tumor associated neutrophils in the development of hepatocellular carcinoma and therapeutic implications Huanxiang Liu 1, # , Dacheng Wang 1, # , Fengsen Wang 1, # , Yulong Zhang 1 , Juntao Liu 1 , Xuezhou Gu 1 , Nan Wang 1 , Endong He 1 , Chengcheng Gao 1 , Honghua Wu 1 , Jiheng Cai 2, ✉ , Guohua Tang 1, ✉ Author information Article notes Copyright and License information 1 Department of General Surgery, Sheyang County People’s Hospital, Yancheng, 224300 China 2 Department of Anesthesiology, Sheyang County People’s Hospital, Yancheng, 224300 China ✉ Corresponding author. # Contributed equally. Received 2026 Jan 31; Accepted 2026 Apr 15; Collection date 2026 Dec. © The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ . PMC Copyright notice PMCID: PMC13230385  PMID: 42012799 Abstract Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death globally, with limited clinical response to conventional therapies and emerging immune checkpoint inhibitors, such as Programmed death receptor-1/programmed death receptor ligand-1 (PD-1/PD-L1) antibodies. In recent years, immunomodulatory cells in the tumor microenvironment (TME) have become a focus of research. Among these, tumor-associated neutrophils (TANs) have been found to play a key role in HCC progression by modulating immune suppression, promoting angiogenesis and facilitating tumor metastasis. Although the role of TANs in various cancers has been extensively studied, systematic reviews on their heterogeneous functions and regulatory mechanisms in HCC remain scarce, and existing studies have yet to comprehensively integrate targeted therapeutic strategies. Therefore, this review aims to fill this research gap by systematically summarizing the current advancements in understanding the origin and functional roles of TANs in HCC, while emphasizing emerging TANs-centered therapeutic strategies to improve immune treatment efficacy and achieve more precise interventions. Keywords: Hepatocellular carcinoma, Tumor-associated neutrophils, Immunotherapy, Tumor microenvironment Introduction In 2022, liver cancer caused over three-quarters of a million deaths globally, making it the third leading cause of cancer-related mortality, behind only lung and colorectal cancers, and the sixth most common cancer diagnosis [ 1 ]. Hepatocellular carcinoma (HCC) represents the dominant type of primary liver cancer, constituting about 75%-85% of all instances [ 2 , 3 ]. The epidemiology of HCC is closely associated with the prevalence of chronic liver diseases, with major etiological factors including chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV), alcohol consumption and metabolic disorders, such as metabolic-associated fatty liver disease (MASLD) [ 4 ]. Additionally, exposure to aflatoxins, alcohol, tobacco and air pollution also significantly contributes to the onset of HCC. Currently, the main treatments for early-stage HCC include liver resection and transplantation [ 5 – 7 ]. Over the past few years, immunotherapy has made significant progress in advanced HCC, fundamentally altering the treatment landscape. Immune checkpoint therapy has emerged as a prominent immunotherapeutic approach for HCC. Immune checkpoint inhibitors (ICIs) work by reversing tumor-induced immune suppression in HCC, thereby restoring and enhancing the ability of T cells to target and eliminate cancer cells. ICIs targeting checkpoint proteins, such as programmed death receptor-1 (PD-1), programmed death receptor ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have shown antitumor responses in HCC [ 8 – 10 ]. Despite the significant advancements in immune checkpoint therapy, its efficacy in HCC remains limited, with only a small fraction of patients showing good responses. Immune evasion and resistance mechanisms are the primary factors contributing to this limited effectiveness, which is associated with insufficient immune cell infiltration in the tumor microenvironment (TME) [ 11 , 12 ]. Therefore, targeting immune cells within the TME, especially neutrophils, appears to be a promising strategy for HCC immunotherapy. Studies have shown that neutrophils actively migrate to the TME along the chemotactic gradient formed by cytokines secreted by tumors, and differentiate into Tumor-associated neutrophils (TANs) under the influence of various cytokines present in the microenvironment [ 13 ]. Compared to other immune cells, TANs exhibit unique heterogeneity and functional plasticity during tumor development, serving as key mediators in regulating the formation of the microenvironment [ 14 ]. TANs not only exert antitumor effects by directly killing tumor cells and activating adaptive immunity but also promote HCC progression through inflammation-driven immune suppression and pre-metastatic microenvironment formation [ 15 ]. It has been reported that TANs are key components of tumor-associated inflammation, supporting the growth, invasion, angiogenesis and metastasis of HCC cells, which are also associated with poor prognosis [ 16 – 19 ]. More importantly, the immunosuppressive properties of TANs and their dual role in tumor promotion under specific conditions make them a potential target for immunotherapy in HCC [ 20 ]. Therefore, exploring the mechanisms underlying the role of TANs not only enhances our understanding of the biological characteristics of HCC, but also provides important research clues for the development of novel immunotherapeutic strategies. Introduction of neutrophils and TANs Neutrophils are essential components of the innate immune system and originate from the hematopoietic cords within the bone marrow [ 21 , 22 ]. Under normal physiological conditions, neutrophils are continuously produced and stored in the bone marrow, with less than 2% of mature neutrophils circulating in the bloodstream [ 23 , 24 ]. In human peripheral circulation, neutrophils make up 50–70% of the circulating white blood cells and are the most abundant immune cells [ 25 , 26 ]. However, the lifespan of neutrophils is typically very short (half-life: 6–8 h), and due to the technical challenges in managing them, their functional heterogeneity in cancer remains ambiguous [ 27 – 29 ]. Neutrophils are typically the first responders at the site of infection and key effectors in cancer defense [ 30 , 31 ]. In response to infection and other stress responses, the bone marrow serves as a storage reservoir for neutrophils and quickly mobilizes the production of large numbers of neutrophils, which cross the endothelial cell barrier into the circulation and migrate to the precise location of the lesion to exert their functions [ 23 ]. The TME consists of various immune cells, cancer-associated fibroblasts, endothelial cells, pericytes and stromal cells [ 32 ]. Immune cells play a significant role, including T cells, natural killer (NK) cells, macrophages and neutrophils, all of which have different functions in antitumor immunity [ 30 , 33 – 36 ]. Neutrophils are key immune cells within the TME, and their role in tumor initiation and progression is quite complex. Neutrophils are capable of sensing various cancer-related signals, such as inflammation and tissue damage, triggering chemotactic responses that recruit them to the tumor site [ 37 ]. The recruitment and migration of neutrophils to the TME are mediated by various factors, including cytokines, chemokines and growth factors. This is an interconnected process, with the classic recruitment cascade involving tethering, rolling, adhesion, crawling and finally, transmigration [ 31 ]. Chemokines produced by the tumor attract neutrophils from the bloodstream, and they then traverse the blood vessel walls to enter the tumor tissue, forming TANs [ 38 – 40 ]. In summary, TANs are neutrophils that infiltrate the tumor. Recent studies have found that the spleen acts as a crucial reservoir for monocytes, with a large number of TAN precursor cells migrating from the spleen to the tumor stroma, further supporting immune responses within the TME [ 41 ]. The role of TANs in tumors is highly complex, as they switch between anti-tumor and pro-tumor phenotypes. In fact, TANs are reprogrammed within the TME to acquire distinct transcriptomic, phenotypic and functional characteristics [ 42 – 44 ]. For instance, Mollinedo et al. proposed that neutrophils can cluster around tumor cells, envelop them and shield them from immune surveillance, and subsequently transport tumor cells from their original site to surrounding tissues in a manner similar to neutrophil transporter in 2019 [ 45 ]. Moreover, inflammatory responses may promote this process by recruiting additional neutrophils that carry tumor cells, with the dying neutrophils potentially serving as food for tumor cells, thereby facilitating tumor metastasis. Increasing evidence suggests that neutrophils in tumors are divided into different subpopulations and exhibit functional polarization or plasticity in the TME. This polarization may have opposing effects at various stages of tumor progression, including initiation, proliferation, metastasis and immune suppression [ 45 , 46 ]. The state of neutrophils is not only tissue-specific but also shows phenotypic plasticity. For example, Fan et al. integrated transcriptomic data from 143 patients across 17 different cancer types, examining 225 neutrophil samples, and identified 10 distinct neutrophil states in cancer [ 47 ]. Three of these states, involved in inflammation, angiogenesis and antigen presentation, were found to dominate across various cancer types, highlighting the diversity and functional complexity of neutrophils within the TME. In addition, the liver possesses unique immune characteristics and has long been considered an organ of immune tolerance. This feature suggests that TANs in the liver may exhibit distinct functional properties compared to those in other tissues. HCC is commonly associated with chronic viral hepatitis, with chronic inflammation being regarded as a key driver of tumorigenesis and metastasis [ 48 , 49 ]. Therefore, as a prototypical inflammation-driven cancer, neutrophils in the TME are thought to play a pivotal role in the progression of HCC [ 50 , 51 ]. Figure 1 illustrates how neutrophils are recruited into HCC and the polarization of neutrophils to TANs. Recent advancements in single-cell technologies have provided deeper insights into the cellular heterogeneity of TANs within the HCC. Xue et al. conducted single-cell RNA sequencing (scRNA-seq) analysis on 160 samples from 124 treatment-naïve HCC patients, identifying 11 distinct neutrophil clusters with different transcriptional profiles [ 27 ]. Notably, clusters Neu_01_MMP8, Neu_07_APOA2, Neu_08_CD74, Neu_09_IFIT1, Neu_10_SPP1, and Neu_11_CCL4 were predominantly located within the tumor. In a related study, Ling et al. identified six distinct TAN subpopulations in MASH-associated HCC tumors, each with unique transcriptomic features, further elucidating the diversity of neutrophils in tumor progression [ 19 ]. Fig. 1. Open in a new tab The formation and classical polarization phenotypes of TANs in the TME. Under the control of granulocyte colony-stimulating factor (G-CSF), neutrophils are continuously generated from bone marrow precursors. Endothelial cells outside the bone marrow produce chemokines that attract mature neutrophils, and facilitate their migration into the circulation. In the TME, when tumor cells are stimulated, the cytokines and chemokines they release create a concentration gradient at the tumor site, promoting the migration of neutrophils from the bloodstream through the vascular wall towards these signaling sources. Additionally, HCC cells promote the release of G-CSF in a paracrine manner, which stimulates the production and secretion of mature neutrophils in the bone marrow. Upon entry into the TME, TGF-β drives the polarization of neutrophils towards the N2 phenotype, while IFN-β induces a shift towards the N1 phenotype, thereby exerting either pro-tumor or anti-tumor effects. This figure was produced using the Figdraw ( www.figdraw.com ) The two most widely studied neutrophil populations in terms of phenotype and function are the TANs that biologically support cancer progression, often referred to as pre-tumor or N2 neutrophils, and those that restrict cancer progression, identified as anti-tumor or N1 neutrophils [ 39 , 52 – 56 ]. The concept was first proposed based on the pioneering work by Fridlender [ 57 ]. In the following years, these two neutrophil phenotype classifications were widely adopted in the literature. In the early stages of tumorigenesis, TANs primarily exhibit the N1 phenotype, demonstrating anti-tumor effects [ 40 ]. However, during the later stages of tumor development, TANs predominantly exhibit the N2 phenotype, which promotes tumor progression, invasion and metastasis [ 58 ]. Further studies have shown that interferon-beta (IFN-β) induces neutrophil polarization towards the anti-tumor N1 phenotype, while transforming growth factor-beta (TGF-β) promotes the production of pro-tumo N2 phenotype [ 57 , 59 ]. It is crucial to highlight that the majority of the research on the N1-N2 concept has primarily been conducted in animal models, whether this classification applies in human oncology remains unclear [ 59 – 61 ]. The correlation between TANs and clinical pathological features In recent years, there has been a growing focus on the study of TANs, particularly their strong correlation with clinical prognosis. For a long time, TANs were believed to possess immunosuppressive properties and contribute to poor prognosis in patients [ 27 , 43 , 62 – 64 ]. Numerous studies have demonstrated that elevated levels of neutrophil infiltration are strongly linked to poor prognosis in most human cancers [ 65 , 66 ]. This phenomenon suggests that TANs may play a crucial role in tumor progression. Reports have also linked neutrophil enrichment in tumors to lymph node metastasis, tumor differentiation and grading, as well as tumor staging [ 38 ]. High expression of TAN characteristics, derived from pan-cancer analysis, significantly predicts poor prognosis for HCC patients in the Cancer Genome Atlas Liver Cancer (TCGA-LIHC) database [ 67 ]. Ling et al. revealed a close association between the high SiglecFhi TAN subgroup and poor prognosis in HCC patients [ 19 ]. More importantly, Zhou et al. tested the effects of TANs on HCC cells both in vitro and in vivo, exploring the mechanisms of their interactions [ 68 ]. They identified a mechanism in which cancer stem-like cells in HCC secrete higher levels of CXCL5, which recruits more TAN infiltration and forms a positive feedback loop. This process may be pivotal in controlling tumor progression and patient prognosis. Furthermore, Zhou collected HCC tissue samples and paired adjacent non-tumor liver tissue from 832 HCC patients for immunohistochemical analysis, revealing that the number of TANs was associated with tumor size, microvascular invasion, tumor capsule, differentiation and staging [ 69 ]. Another research shows that overexpression of CRKL in HCC promotes the expression of VEGFα and CXCL1 by stabilizing β-catenin, leading to increased infiltration of TANs in the tumor and correlating with poor prognosis and reduced CD8 + T cell infiltration in HCC patients [ 70 ]. Therefore, TANs not only play a key role in the immune microenvironment, but their quantity and activity are closely related to the clinical and pathological features of HCC. The mechanisms by which TANs regulate the progression of HCC TANs play a complex dual role in tumor initiation and progression, with the ability to either promote or inhibit tumor growth through various mechanisms. In the TME, neutrophils contribute to tumor progression by mechanisms such as extracellular matrix degradation, immune suppression, tumor cell proliferation, increased metastasis and angiogenesis [ 25 , 71 – 73 ]. Moreover, neutrophils are recruited to the site of the lesion, where they release proteases and generate large amounts of reactive oxygen species (ROS) [ 74 ]. This makes the tissue more susceptible to pathogen invasion and may even lead to chronic inflammation, thereby promoting cancer through tissue destruction. Neutrophils are activated via various mechanisms to kill bacterial pathogens, including phagocytosis, degranulation of antimicrobial factors and the release of neutrophil extracellular traps (NETs) [ 31 , 75 , 76 ]. Neutrophil elastase (NE), as part of the cargo of neutrophil degranulation, directly promotes tumor cell proliferation and migration, thereby driving tumor growth and metastasis [ 77 ]. Although TANs can promote tumor progression, some studies suggest that TANs can also counteract cancer development by directly killing tumor cells or activating both innate and adaptive immunity [ 58 , 76 ]. Anti-tumor neutrophils exert their effects through multiple mechanisms, including the induction of antibody-dependent cellular cytotoxicity (ADCC), direct cytotoxicity and the activation of anti-tumor adaptive immunity [ 78 , 79 ]. Additionally, in the TME, neutrophils may inhibit tumor progression by producing antitumor factors such as hydrogen peroxide, nitric oxide (NO) and thrombospondin-1 (TSP-1) [ 34 , 80 , 81 ]. Based on their immune characteristics, TANs can be classified into two subtypes: N1 and N2, which are associated with antitumor and protumor effects, respectively. N1 TANs are characterized by high levels of TNF-α, CCL3, ICAM-1 and low levels of arginase axis [ 56 ]. Antitumor N1 TANs regulate tumor growth through various mechanisms, such as cytotoxicity against tumor cells, tumor cell apoptosis, tumor rejection response, metastasis inhibition and enhancement of antitumor immune responses [ 77 , 78 , 82 ]. Specifically, N1 TANs enhance tumor cell toxicity, reduce immune suppression and inhibit tumor development by producing TNF-α, ICAM-1, ROS, myeloperoxidase (MPO), apoptosis-related factors and reducing arginase expression [ 38 , 83 – 85 ]. In contrast, N2 TANs exhibit protumor characteristics that promote tumor growth. N2 TANs are characterized by the upregulation of chemokines such as CCL2, CCL3, CCL4, CCL8, CCL12 and CCL17, as well as CXCL1, CXCL2, IL-8/CXCL8 and CXCL16, etc [ 56 ]. Protumor N2 TANs contribute to various aspects of tumor growth, including angiogenesis, tumor invasion, metastasis, oxidative damage and suppression of cytotoxic T lymphocyte function through the synthesis and secretion of proteases and the release of cytokines and chemokines [ 71 , 78 , 82 ]. Moreover, N2 TANs further promote tumor migration and metastasis by expressing arginase, matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF) and chemokines [ 57 , 65 , 86 ]. These findings suggest that tumors and the TME regulate the recruitment of neutrophils, and TANs regulate tumor progression. In HCC, TANs promote tumor growth and metastasis through various mechanisms. The chemokine CXCL5 is upregulated in HCC patients and recruits neutrophils, thereby promoting tumor progression via the activation of the PI3K-Akt and ERK1/2 signaling pathways [ 17 , 87 ]. Research has indicated that an elevated expression of CXCL5 is strongly linked to higher neutrophil content, shorter overall survival (OS) and tumor recurrence in HCC samples. CXCL5 acts as a chemoattractant in vitro, attracting neutrophils to the tumor site, thereby further enhancing tumor proliferation and metastasis. Furthermore, the recruitment of neutrophils is also closely related to other molecules. For instance, MMP-9 can further accelerate angiogenesis in liver, lung and pancreatic cancers by promoting neutrophil recruitment, thus facilitating tumor growth and metastasis [ 88 ]. Additionally, the pro-inflammatory cytokine IL-17 also plays an important role in the TME. IL-17 promotes neutrophil accumulation in the surrounding tumor tissue by generating chemokines or activating γδT cells, further driving tumor progression [ 16 ]. Research by Qin et al. has demonstrated that the accumulation of acetyl-CoA induces the upregulation of chemokine CXCL1, which recruits TANs, leading to the formation of NETs and promoting the metastasis of HCC [ 89 ]. Moreover, TANs recruit macrophages and T regulatory cells through the secretion of CCL2 and CCL17, which infiltrate the TME and stimulate angiogenesis, thereby promoting HCC growth and metastasis [ 90 ]. Under the action of neutrophils, signaling pathways in the TME are activated, promoting tumor proliferation and metastasis. For example, neutrophils enhance the autophagic process by activating the Erk1/2, p38 and NF-κB signaling pathways, thereby increasing neutrophil survival and promoting tumor cell growth [ 18 ]. Additionally, studies have shown that neutrophils migrate to the liver after induction of the oncogenic k-ras (V12) expression in a transgenic zebrafish model [ 91 ]. Time-lapse video analysis revealed that neutrophils migrate slowly along the tumor margins, but are relatively quiescent upon entry into the liver. This phenomenon is associated with increased expression of TGF-β1a and reduced anti-tumor activity of TANs, suggesting that neutrophils play a pro-tumor role in the TME. Ling et al. discovered that the pro-tumor SiglecFhi subset of neutrophils is enriched at the tumor site in MASH-related HCC [ 19 ]. These SiglecFhi neutrophils directly interact with tumor cells, enhance their self-renewal potential and promote proliferation and migration of HCC cells, thus driving tumor progression. Furthermore, SiglecFhi TANs secrete TGF-β to inhibit the presentation of tumor antigens, further promoting the aggressiveness of HCC. Overall, TANs play a significantly detrimental role in MASH-related HCC, promoting tumor growth and metastasis. Therefore, TANs can recruit, activate and enhance tumor immune evasion and metastatic abilities through various mechanisms, making them become potential therapeutic targets in cancer treatment. Therapeutic strategies based on TANs In tumor immunotherapy, TANs are characterized by their short half-life, which helps to reduce the likelihood of them being reprogrammed as immunosuppressive cells within the TME. This feature contrasts with longer-lived immune cells, which are at a higher risk of being converted into immune escape cells, thereby offering potential opportunities for immunotherapy. The main strategies for targeting TANs in the treatment of HCC are shown in Fig. 2 . Fig. 2. Open in a new tab Blocking TANs Recruitment: CXCR2 is a major chemokine receptor that attracts neutrophils into the tumor microenvironment. Chemokines such as CXCL1, CXCL2, CXCL5 and CRKL promote neutrophil migration from peripheral blood into tumor tissues by binding to CXCR2. CXCR2 inhibitors (such as SB225002, AZ10397767), CRKL inhibitors and CXCL5 inhibitors effectively block the delivery of TANs to the tumor microenvironment, reduce TANs infiltration, promote CD8 + T cell activation, and enhance the anti-tumor activity of T cells. The figure was created using the Figdraw ( www.figdraw.com ) Inhibiting the recruitment and survival of TANs TANs play a complex role in the tumor immune microenvironment. Firstly, cytokines such as TNF-α and interferon (IFN) have been shown to activate TANs, enhancing their direct cytotoxicity against tumor cells. TNF-α exerts its effect through the tumor necrosis factor receptor (TNFR) signaling pathway on TANs. Upon activation of this pathway, hepatocyte growth factor (HGF) and MET kinase activation further promote the production of nitric oxide (NO), which subsequently kills tumor cells via an NO-dependent mechanism [ 81 ]. Although TANs exhibit antitumor activity under certain conditions, in many cases, they promote tumor initiation and progression through immune evasion mechanisms. Inhibiting the recruitment and survival of TANs has emerged as a strategy to enhance the effectiveness of immunotherapy. Ling et al. discovered that high abundance of SiglecFhi TANs could downregulate MHCI in tumor cells, reducing antigen presentation and aiding tumor cells in evading T cell recognition. Consequently, the removal of SiglecFhi TANs increased the immunogenicity of the mash-related HCC model and made it more sensitive to immunotherapy [ 19 ]. Therefore, the unprecedented role of SiglecFhi TANs in enhancing the immune evasion capability of invasive tumor phenotypes makes them a crucial target for immunotherapy. In addition, the mobilization, migration and recruitment of TANs play a crucial role in tumor initiation and progression, which are primarily regulated by CXCR2. For instance, the CXCR2 selective inhibitor SB225002 significantly reduces TAN infiltration, promotes CD8 + T cell activation and enhances T cell-mediated anti-tumor activity [ 86 ]. The CXCR2-specific small molecule inhibitor AZ10397767 significantly reduces the number of TANs and inhibits tumor growth in both in vivo and in vitro lung cancer models, suggesting that CXCR2 inhibitors may be a promising therapeutic approach for lung cancer [ 92 ]. Therefore, blocking CXCR2 to inhibit TANs in tumors has become an important strategy to improve the efficacy of immunotherapy. Li et al. found that CT10 regulator of kinase-like (CRKL), which is significantly upregulated in PD-1 resistant HCC, contributes to increased recruitment of TANs, thereby diminishing the infiltration and activation of cytotoxic CD8 + T lymphocytes and promoting resistance to anti-PD-1 therapy [ 70 ]. Consequently, CRKL inhibitors combined with anti-PD-1 therapy may be developed for HCC treatment. Furthermore, studies in mouse models and HCC samples confirmed that sorafenib-induced hypoxia activates NF-κB signaling to enhance the secretion of CXCL5 from HCC cells, promoting TANs infiltration and recruiting macrophages and regulatory T cells, thereby facilitating HCC progression and sorafenib resistance [ 90 ]. Patients with fewer TANs are more likely to respond to sorafenib treatment, suggesting that TANs can serve as a predictive biomarker for sorafenib response. Additionally, TANs depletion can enhance the anti-HCC effects of sorafenib. CXCL5 promotes HCC cell proliferation, invasion and intratumoral neutrophil infiltration, helping the tumor escape immune surveillance [ 17 ]. Knockdown of CXCL5 inhibits cell invasion and epithelial-mesenchymal transition (EMT) capabilities in the HuH-7 HCC cell line [ 93 ]. Therefore, CXCL5 inhibitors have the potential to improve the immune response in HCC, slow tumor growth and inhibit metastasis. With further research, CXCL5 inhibitors may become novel targeted drugs for HCC therapy, particularly when used in combination with ICIs, which may significantly improve the therapeutic effect. Figure 3 illustrates the blockade of TANs recruitment by relevant inhibitors, thereby enhancing anti-tumor activity. Fig. 3. Open in a new tab Therapeutic strategies targeting TANs in HCC. (1) Inhibition of neutrophil recruitment to HCC. (2) Regulation of neutrophil polarization. (3) Combination therapy. (4) Neutrophil-based drug delivery. (5) Inhibition of NET formation. The figure was created using the Figdraw ( www.figdraw.com ) Reprogramming TANs and reversing TAN polarization In recent years, reprogramming the polarization state of TANs, especially the transformation of pro-tumor N2 TANs into anti-tumor N1 TANs, has been regarded as a promising immunotherapy strategy. By targeting specific cytokine pathways, it is possible to effectively reverse the polarization of TANs, enhance their anti-tumor functions and increase their cytotoxicity against tumor cells. N2 TANs are characterized by high expression of PD-L1, secretion of arginase-1 (ARG1) and ROS, and inducible nitric oxide synthase (iNOS), all of which suppress the anti-tumor functions of effector T cells and reduce the response to ICIs [ 94 ]. Therefore, targeting TANs or blocking the polarization towards a pro-tumor phenotype can enhance the efficacy of immunotherapy. Related studies have found that DTX2 promotes HCC cells to secrete CXCL2 and CXCL6, which recruit neutrophils and polarize them towards a pro-tumor phenotype, thereby suppressing the proliferation and cytotoxicity of CD8 + T cells and weakening the sensitivity of HCC cells to PD1-based immunotherapy [ 95 ]. Consequently, DTX2 inhibitors therapy inhibit tumor growth, while DTX2 can be identified as a potential target for HCC immunotherapy. Additionally, Qin et al. discovered that CXCL9 promotes N1 polarization of neutrophils and restores its antitumor activity through CXCR3 in HCC [ 96 ]. Targeting the CXCL9/CXCR3 axis represents a novel immunotherapy strategy for HCC. However, the strategy of altering the polarization state of TANs is not limited to targeting cytokine pathways but also includes reprogramming neutrophil function through antibody-based immunotherapy. Studies have shown that monoclonal antibodies (mAbs), upon binding to tumor-associated antigens (TAAs), interact with the Fc receptor (FcR) expressed on immune cells or neutrophils through their Fc tail, thereby activating neutrophils [ 65 ]. Once activated, neutrophils release cytotoxic substances, including proteases, defensins, TNF-α, hydrogen peroxide (H2O2), hypochlorous acid (HOCl) and MPO, which can directly kill tumor cells. Furthermore, the inflammatory mediators and chemokines released by neutrophils, including IL-8, growth-regulated oncogene (GRO-α), defensins, monocyte chemoattractant protein (MCP) and macrophage inflammatory proteins (MIP-1α and MIP-1β), can attract other immune cells, thereby enhancing the immune response. These mechanisms provide theoretical support for neutrophil-based anti-tumor immunotherapies. Additionally, the concept of N1-N2 polarization further provides new therapeutic targets for reprogramming neutrophil functions. Researchers have proposed several hypotheses, such as the use of antibodies to inactivate pre-tumor inducers under the regulation of TGF-β or stimulate anti-tumor N1 TANs. Particularly during treatment, these approaches may lead to significant clinical benefits [ 97 ]. Combined treatment enhance the therapeutic effect Studies have shown that the number and functional status of TANs directly influence the efficacy of immunotherapy, particularly in the context of ICIs such as PD-1/PD-L1 inhibitors. Patients with high levels of TANs may exhibit weaker immune responses to therapy, suggesting that TANs play a significant role in the immune evasion process. Therefore, it is crucial to consider the impact of TANs when developing immunotherapeutic strategies. Infiltrating neutrophils, especially PD-L1-positive neutrophils, are more prevalent in the TME. In HCC, the interaction between PD-L1 + neutrophils and PD-1 + T cells can suppress T cell proliferation and activation. Studies indicate that the proportion of PD-L1 + neutrophils and PD-1 + T cells in the peritumoral tissue is higher, and this ratio is closely associated with disease-free survival (DFS) [ 98 ]. Blocking PD-L1 can partially reverse these inhibitory effects, restore T cell activity and thereby enhance anti-tumor immune responses. Furthermore, the CXCR2 inhibitor AZD5069, when combined with anti-PD-1 antibodies, increases neutrophil numbers and selectively reprograms TANs from a pro-tumor to an anti-tumor phenotype, reducing tumor burden and improving the efficacy of anti-PD-1 therapy in non-alcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) [ 99 ]. Therefore, therapeutic strategies targeting TANs can be combined with other immunotherapies, such as T cell therapies or antibody-based treatments, to enhance overall efficacy. Preclinical studies have indicated that this combined strategy holds significant potential, which can improve treatment response rates in liver cancer patients. Xu et al. employed single-cell RNA sequencing and a prospective clinical cohort to collect tumor samples from 10 HCC patients receiving atezolizumab and bevacizumab combination therapy [ 100 ]. The study found that Galectin-4 overexpression promotes metabolic adaptation and the formation of an immunosuppressive tumor microenvironment, which facilitates the accumulation of PD-L1 + TANs, thereby counteracting the efficacy of treatment. Therefore, elucidating the mechanisms of TANs-mediated resistance and optimizing combination strategies will pave the way for precision immunotherapy in HCC [ 101 ]. Currently, numerous clinical trials are evaluating combination therapies targeting TANs to enhance the effectiveness of immunotherapy. Drug delivery systems targeting TANs Sensitive drug delivery nanosystems offer a promising strategy for the on-demand release of conventional drugs to avoid side effects in the TME [ 102 ]. Fan et al. proposed that HLA-DR+ neutrophils exhibit significant amino acid metabolic enrichment, including valine, leucine and isoleucine [ 47 ]. Leucine-based diets or adoptive delivery strategies can enhance cancer immunotherapy efficacy and may serve as a potential neutrophil-based therapeutic strategy. Their therapeutic strategy offers the following advantages: First, the neutrophil delivery strategy only requires the classification and short-term in vitro stimulation of circulating neutrophils. This approach is safer and does not make patients more susceptible to infections. Second, HLA-DR+ neutrophils can load a broad spectrum of (neo)antigens without the need for complex genetic engineering. This advantage makes neutrophil-based therapy more promising for immunotherapy. Third, considering the short half-life of neutrophils, the side effects of this therapy may be transient and controllable. This feature may minimize the duration of any potential side effects, allowing for timely intervention and adjustment of the treatment strategy. An attractive application of neutrophils in cancer therapy is the use of their unique chemotactic properties to replicate genetic material into specifically targeted drug carriers. Leveraging these properties, along with their high mobility and ability to cross the blood-brain barrier, neutrophils have emerged as outstanding candidate carriers in nanoparticle-based therapies [ 103 ]. A new acidic/photo-sensitive DC-based neoantigen nano-vaccine targeting TANs has been explored for its potential to enhance anti-cancer immune responses and improve the efficacy of HCC immunotherapy, effectively converting the “cold” state of tumor immunity into a “hot” state [ 104 ]. This strategy provides valuable insights into the design of personalized cancer vaccines for HCC immunotherapy. Furthermore, neutrophil membrane-derived nanovesicles, as alternatives to extracellular vesicles, have shown great promise in cancer treatment, offering more effective and scalable drug delivery. Overall, drug delivery systems can be classified into two categories: neutrophils as carriers and nanovesicles derived from cell membranes, both of which provide innovative solutions for cancer therapy [ 103 , 105 ]. The system of neutrophil extracellular traps A particularly interesting strategy targeting N2 neutrophils involves the blockade of NETs, which play an important biological role [ 106 ]. NETs are web-like structures composed of DNA fibers containing antimicrobial substances secreted by neutrophils during the process of NETosis and granule-derived antimicrobial proteins, such as neutrophil elastase, cathepsin G and MMP-9 [ 107 ]. These structures function to capture and neutralize pathogens, including fungi, bacteria and viruses [ 108 ]. NETosis is a form of neutrophil death where dying neutrophils excrete their DNA and antimicrobial substances, forming NETs to trap nearby microorganisms [ 109 ]. However, whether NETosis is properly regulated, or whether it is an all-or-nothing response, remains an unresolved issue. Importantly, NETosis is considered a pro-inflammatory process and is closely associated with pathological processes such as pyroptosis and necrosis [ 110 , 111 ]. Recent studies have shown that NETs not only involved in immune defense but also play a crucial role in cancer metastasis. NETs assist tumor metastasis by capturing circulating tumor cells (CTCs), promoting cancer cell invasion and awakening dormant cancer cells [ 51 , 112 – 114 ]. Moreover, NET-related high-mobility group proteins, such as HMGB1, NE and MMP-9, have also been shown to induce cancer cell proliferation [ 115 ]. In recent years, an increasing number of studies have shown that the formation of NETs plays a crucial role in the occurrence, progression and metastasis of HCC. Table 1 summarizes the major outcomes of the studies describing NETs in HCC. Although these studies are still in the preliminary stages, the formation of NETs has been found to be associated with various clinical features in HCC patients, particularly in those with HBV-induced liver cancer, post-liver surgery patients, and those suffering from non-alcoholic steatohepatitis (NASH) and liver cirrhosis, where NET concentrations are significantly elevated [ 116 ]. It has been shown that NET-DNA (DNA from NETs) can impair antitumor immune responses by interacting with the transmembrane and coiled-coil domain 6 (TMCO6) on CD8 + T cells, thereby promoting the progression of HCC [ 117 ]. Therefore, targeting this signaling pathway could serve as a novel immune therapeutic strategy to block the progression of HCC. Therapeutic strategies targeting NETs hold great promise. Approaches to inhibit NETosis or remove existing NETs offer a new treatment avenue for managing HCC. Studies have demonstrated that the combination of DNase I and aspirin more effectively inhibits NET formation and significantly reduces HCC metastasis in mouse models, highlighting their potential in combating HCC metastasis [ 118 ]. Furthermore, the prospects of targeting NETs as a therapeutic approach for HCC are also very promising, as blocking NET formation can effectively prevent liver cancer progression, inhibit metastasis, reduce cancer-associated thrombosis and decrease postoperative recurrence [ 116 ]. By further understanding the role of TANs in HCC and exploring their relationship with NETs, it is hoped that more precise cancer treatments can be developed. Table 1. Summary of the included studies of NETs in HCC Study design Animal models Cell type Major outcomes/findings Authors In vivo, in vitro, and ex vivo Mouse Human liver cell line QSG-7701, HepG2 and HepG2.2.15, human umbilical vein endothelial cell line HUVEC and the mouse HCC cell line H22 The levels of NETs are elevated in the serum and tissue specimens of HCC patients, particularly those infected with HBV. HBV-induced S100A9 accelerates the production of NETs, which subsequently promotes the growth and metastasis of HCC cells. Zhan et al. [ 119 ] In vivo, in vitro, and ex vivo Mouse Human cell line HepG2 and L02, human cell line MHCC97H and mice cell line Hepa1-6 HCC cells trigger the formation of NETs in normal neutrophils. NETs not only capture HCC cells but also further induce resistance to cell death and enhance invasive capacity through the LR4/9-COX2 signaling pathway, thereby triggering their metastatic potential. Yang et al. [ 118 ] In vitro, and ex vivo Mouse / DNase treatment can inhibit the formation of NETs, and the suppression of NETs can slow down the progression of NASH to HCC. Windt et al. [ 120 ] In vivo, in vitro, and ex vivo Mouse Human HepG2, Hep3B, PLC, Hepa1-6 and HEK293T cells, THLE3 cells The secreted protease PRSS35 can suppress the protein levels of CXCL2, thereby reducing neutrophil recruitment to the tumor and the formation of NETs, ultimately inhibiting the progression of HCC. Wang et al. [ 121 ] In vitro, and ex vivo Mouse / NETs are primarily distributed in the immune-rich regions of HCC. By activating NF-κB, NETs upregulate CD73 in HCC, promoting the infiltration of regulatory T cells (Tregs) to mediate immune evasion in HCC. Treatment with DNase I can inhibit the effects of NETs and enhance the therapeutic efficacy of anti-programmed cell death protein 1 (PD-1). Yu et al. [ 122 ] In vivo, in vitro, and ex vivo Mouse Tumor cell lines (HepG2, QGY-7703, SK-Hep-1, Hela, and Hepa1-6), Human normal liver cell-line HL-7702 TANs undergo a metabolic shift induced by the tumor, favoring glycolysis and the pentose phosphate pathway. This metabolic reprogramming subsequently induces the production and release of NETs, promoting tumor metastasis in human HCC. Depletion of NETs can inhibit tumor metastasis in mice. Zhou et al. [ 123 ] Both in vivo and in vitro Mouse HCC cells HepG2, SMMC-7721, and MHCC‐97 H, the normal hepatocyte cell line LO2, and HL‐60 The m6A methyltransferase METTL5 accelerates the malignant progression of HCC by promoting the production and release of NETs. Wang et al. [ 124 ] In vivo, in vitro, and ex vivo Mouse The mouse HCC cell line Hepa1-6 PPARα can limit mitochondrial oxidative stress, inhibit the cGAS-STING-NF-κB signaling pathway, and restrict the release of NETs. This ultimately enhances the interaction between antitumor leukocytes and HCC cells, thereby limiting tumor growth. Pan et al. [ 125 ] Open in a new tab Challenges and future directions Precise regulation of TANs function: Specific markers need to be developed to distinguish the N1/N2 subpopulations, in order to avoid comprehensive clearance of immunodeficiency caused by neutrophils. Spatiotemporal heterogeneity: The functional differences of TANs at various stages of HCC development and in different tumor locations need to be further analyzed. Clinical studies are required to reveal the role of TANs in diverse tumor microenvironments, allowing for the development of tailored treatment strategies for different types of liver cancer patients. Clinical translation barriers: The role of TANs in current preclinical models such as mouse HCC models differs from that in humans, necessitating the optimization of experimental systems. Moreover, future research should focus on clinical trials targeting TANs to evaluate the safety and efficacy of TANs-targeted therapies. Multi-omics and single-cell technologies: Integrating single-cell sequencing technologies with spatial transcriptomics will provide comprehensive insights into the complex interactions between TANs and other immune cells. This approach will facilitate a deeper understanding of the dynamic changes in the liver immune microenvironment and may lead to the identification of new immunotherapeutic targets. By exploring the interaction between immune cells, more precise immunotherapy strategies for HCC can be developed. Conclusion TANs play a pivotal role as regulators in the HCC immune microenvironment, and targeting TANs holds the potential to break through the limitations of current immunotherapies. By precisely regulating the polarization status of TANs or combining targeted strategies, more effective individualized treatments for HCC patients may be achieved. Future research needs to deeply analyze the dynamic regulatory mechanisms of TANs and advance translational medical research to accelerate clinical validation. Acknowledgements The Figures were created by Figdraw ( www.figdraw.com ). Abbreviations HCC Hepatocellular carcinoma PD-1 Programmed death receptor-1 PD-L1 Programmed death receptor ligand-1 TME Tumor microenvironment TANs Tumor-associated neutrophils HBV Hepatitis B virus HCV Hepatitis C virus MASLD Metabolic-associated fatty liver disease ICIs Immune checkpoint inhibitors CTLA-4 Cytotoxic T-lymphocyte-associated protein 4 NK Natural killer IFN-β Interferon-beta TGF-β Transforming growth factor-beta ROS Reactive oxygen species NE Neutrophil elastase NETs Neutrophil extracellular traps ADCC Antibody-dependent cellular cytotoxicity TSP-1 Thrombospondin-1 MPO Myeloperoxidase MMP-9 Matrix metalloproteinase-9 VEGF Vascular endothelial growth factor OS Overall survival INF Interferon TNFR Tumor necrosis factor receptor HGF Hepatocyte growth factor NO Nitric oxide CRKL CT10 regulator of kinase-like EMT Epithelial-mesenchymal transition ARG1 Arginase-1 iNOS Inducible nitric oxide synthase TAAs Tumor-associated antigens DFS Disease-free survival CTCs Circulating tumor cells NASH Non-alcoholic steatohepatitis Author contributions All authors contributed to the study’s conception and design. HL, DW and FW wrote the manuscript and drew the figures. HL, YZ, JL, XG, NW, CG, EH and HW collected the related papers, created the Tables, and helped to revise the manuscript. JC and GT designed and revised the manuscript. All the authors read and approved the final version of the review. All authors read and approved the final manuscript. Funding This work was funded by the Yancheng Municipal Health Commission Medical Research Key Project (YK2023039), the Yancheng Science and Technology Bureau natural science foundation project (YCKY2024080), and the Bethune Foundation Mercy Medical Research Project on Pain Management (ezmr2024-060). Data availability No datasets were generated or analysed during the current study. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Footnotes Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Huanxiang Liu, Dacheng Wang and Fengsen Wang have contributed equally to this research. Contributor Information Jiheng Cai, Email: cjhtop1@163.com. Guohua Tang, Email: drtangguohua@163.com. References 1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229–63. [ DOI ] [ PubMed ] [ Google Scholar ] 2. de Martel C, Georges D, Bray F, et al. Global burden of cancer attributable to infections in 2018: a worldwide incidence analysis. Lancet Glob Health. 2020;8(2):e180–90. [ DOI ] [ PubMed ] [ Google Scholar ] 3. Rumgay H, Ferlay J, de Martel C, et al. Global, regional and national burden of primary liver cancer by subtype. Eur J Cancer. 2022;161:108–18. [ DOI ] [ PubMed ] [ Google Scholar ] 4. Singh SP, Madke T, Chand P. Global Epidemiology of Hepatocellular Carcinoma. J Clin Exp Hepatol. 2025;15(2):102446. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 5. Zheng J, Wang S, Xia L, et al. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther. 2025;10(1):35. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 6. Luo WL, Wang QB, Li YK, et al. Impact of Middle Hepatic Vein Resection During Hemihepatectomy on Surgical Outcomes and Long-Term Prognosis in Hepatocellular Carcinoma: A Retrospective Study. J Hepatocell Carcinoma. 2025;12:2681–92. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 7. Wang QB, Luo WL, Li YK, et al. Tumor Compression of the Hepatic or Portal Vein Predicts the Presence of Microvascular Invasion and Satellite Nodules in Hepatocellular Carcinoma: A Retrospective Study. J Hepatocell Carcinoma. 2025;12:2055–67. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 8. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492–502. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 9. Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940–52. [ DOI ] [ PubMed ] [ Google Scholar ] 10. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 2022;1(8):EVIDoa2100070. [ DOI ] [ PubMed ] [ Google Scholar ] 11. Yu SJ. Immunotherapy for hepatocellular carcinoma: Recent advances and future targets. Pharmacol Ther. 2023;244:108387. [ DOI ] [ PubMed ] [ Google Scholar ] 12. Hegde PS, Karanikas V, Evers S. The Where, the When, and the How of Immune Monitoring for Cancer Immunotherapies in the Era of Checkpoint Inhibition. Clin Cancer Res. 2016;22(8):1865–74. [ DOI ] [ PubMed ] [ Google Scholar ] 13. Saha S, Biswas SK. Tumor-Associated Neutrophils Show Phenotypic and Functional Divergence in Human Lung Cancer. Cancer Cell. 2016;30(1):11–3. [ DOI ] [ PubMed ] [ Google Scholar ] 14. Li L, Zhao L, Cao K et al. Hepatocytes functionally reprogrammed by KIAA1199-high colorectal cancer cells favour the accumulation of pro-metastatic Egr1(+) neutrophils. Nat Commun. 2026. [ DOI ] [ PMC free article ] [ PubMed ] 15. Fan G, Na J, Shen Z, et al. Heterogeneity of tumor-associated neutrophils in hepatocellular carcinoma. Mol Immunol. 2025;177:1–16. [ DOI ] [ PubMed ] [ Google Scholar ] 16. Kuang DM, Zhao Q, Wu Y, et al. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J Hepatol. 2011;54(5):948–55. [ DOI ] [ PubMed ] [ Google Scholar ] 17. Zhou SL, Dai Z, Zhou ZJ, et al. Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. Hepatology. 2012;56(6):2242–54. [ DOI ] [ PubMed ] [ Google Scholar ] 18. Li XF, Chen DP, Ouyang FZ, et al. Increased autophagy sustains the survival and pro-tumourigenic effects of neutrophils in human hepatocellular carcinoma. J Hepatol. 2015;62(1):131–9. [ DOI ] [ PubMed ] [ Google Scholar ] 19. Teo JMN, Chen Z, Chen W et al. Tumor-associated neutrophils attenuate the immunosensitivity of hepatocellular carcinoma. J Exp Med 2025;222(1). [ DOI ] [ PMC free article ] [ PubMed ] 20. Lecot P, Sarabi M, Pereira Abrantes M, et al. Neutrophil Heterogeneity in Cancer: From Biology to Therapies. Front Immunol. 2019;10:2155. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 21. Burn GL, Foti A, Marsman G, et al. Neutrophil Immun. 2021;54(7):1377–91. [ DOI ] [ PubMed ] [ Google Scholar ] 22. Ballesteros I, Rubio-Ponce A, Genua M, et al. Co-option of Neutrophil Fates by Tissue Environments. Cell. 2020;183(5):1282–e9718. [ DOI ] [ PubMed ] [ Google Scholar ] 23. Burdon PC, Martin C, Rankin SM. Migration across the sinusoidal endothelium regulates neutrophil mobilization in response to ELR + CXC chemokines. Br J Haematol. 2008;142(1):100–8. [ DOI ] [ PubMed ] [ Google Scholar ] 24. Semerad CL, Liu F, Gregory AD, et al. G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood. Immunity. 2002;17(4):413–23. [ DOI ] [ PubMed ] [ Google Scholar ] 25. Coffelt SB, Wellenstein MD, de Visser KE. Neutrophils in cancer: neutral no more. Nat Rev Cancer. 2016;16(7):431–46. [ DOI ] [ PubMed ] [ Google Scholar ] 26. Borregaard N. Neutrophils, from marrow to microbes. Immunity. 2010;33(5):657–70. [ DOI ] [ PubMed ] [ Google Scholar ] 27. Xue R, Zhang Q, Cao Q, et al. Liver tumour immune microenvironment subtypes and neutrophil heterogeneity. Nature. 2022;612(7938):141–7. [ DOI ] [ PubMed ] [ Google Scholar ] 28. Summers C, Rankin SM, Condliffe AM, et al. Neutrophil kinetics in health and disease. Trends Immunol. 2010;31(8):318–24. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 29. Eruslanov EB, Singhal S, Albelda SM. Mouse versus Human Neutrophils in Cancer: A Major Knowledge Gap. Trends Cancer. 2017;3(2):149–60. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 30. Treffers LW, Hiemstra IH, Kuijpers TW, et al. Neutrophils in cancer. Immunol Rev. 2016;273(1):312–28. [ DOI ] [ PubMed ] [ Google Scholar ] 31. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13(3):159–75. [ DOI ] [ PubMed ] [ Google Scholar ] 32. de Visser KE, Joyce JA. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell. 2023;41(3):374–403. [ DOI ] [ PubMed ] [ Google Scholar ] 33. Binnewies M, Roberts EW, Kersten K, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24(5):541–50. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 34. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14(10):1014–22. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 35. Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science. 2015;348(6230):74–80. [ DOI ] [ PubMed ] [ Google Scholar ] 36. Lei X, Lei Y, Li JK, et al. Immune cells within the tumor microenvironment: Biological functions and roles in cancer immunotherapy. Cancer Lett. 2020;470:126–33. [ DOI ] [ PubMed ] [ Google Scholar ] 37. Hedrick CC, Malanchi I. Neutrophils in cancer: heterogeneous and multifaceted. Nat Rev Immunol. 2022;22(3):173–87. [ DOI ] [ PubMed ] [ Google Scholar ] 38. Zhou J, Liu H, Jiang S, et al. Role of tumor-associated neutrophils in lung cancer (Review). Oncol Lett. 2023;25(1):2. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 39. Bronte V, Brandau S, Chen SH, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7:12150. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 40. Eruslanov EB, Bhojnagarwala PS, Quatromoni JG, et al. Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer. J Clin Invest. 2014;124(12):5466–80. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 41. Cortez-Retamozo V, Etzrodt M, Newton A, et al. Origins of tumor-associated macrophages and neutrophils. Proc Natl Acad Sci U S A. 2012;109(7):2491–6. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 42. Ng LG, Ostuni R, Hidalgo A. Heterogeneity of neutrophils. Nat Rev Immunol. 2019;19(4):255–65. [ DOI ] [ PubMed ] [ Google Scholar ] 43. Ng MSF, Kwok I, Tan L, et al. Deterministic reprogramming of neutrophils within tumors. Science. 2024;383(6679):eadf6493. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 44. Siwicki M, Pittet MJ. Versatile neutrophil functions in cancer. Semin Immunol. 2021;57:101538. [ DOI ] [ PubMed ] [ Google Scholar ] 45. Mollinedo F. Neutrophil Degranulation, Plasticity, and Cancer Metastasis. Trends Immunol. 2019;40(3):228–42. [ DOI ] [ PubMed ] [ Google Scholar ] 46. Cerezo-Wallis D, Ballesteros I. Neutrophils in cancer, a love-hate affair. FEBS J. 2022;289(13):3692–703. [ DOI ] [ PubMed ] [ Google Scholar ] 47. Wu Y, Ma J, Yang X, et al. Neutrophil profiling illuminates anti-tumor antigen-presenting potency. Cell. 2024;187(6):1422–e3924. [ DOI ] [ PubMed ] [ Google Scholar ] 48. Tu T, Buhler S, Bartenschlager R. Chronic viral hepatitis and its association with liver cancer. Biol Chem. 2017;398(8):817–37. [ DOI ] [ PubMed ] [ Google Scholar ] 49. Mantovani A, Allavena P, Sica A, et al. Cancer-related inflammation. Nature. 2008;454(7203):436–44. [ DOI ] [ PubMed ] [ Google Scholar ] 50. Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 51. Park J, Wysocki RW, Amoozgar Z, et al. Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps. Sci Transl Med. 2016;8(361):361ra138. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 52. Brandau S, Dumitru CA, Lang S. Protumor and antitumor functions of neutrophil granulocytes. Semin Immunopathol. 2013;35(2):163–76. [ DOI ] [ PubMed ] [ Google Scholar ] 53. Sionov RV, Fainsod-Levi T, Zelter T, et al. Neutrophil Cathepsin G and Tumor Cell RAGE Facilitate Neutrophil Anti-Tumor Cytotoxicity. Oncoimmunology. 2019;8(9):e1624129. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 54. Mantovani A. The yin-yang of tumor-associated neutrophils. Cancer Cell. 2009;16(3):173–4. [ DOI ] [ PubMed ] [ Google Scholar ] 55. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012;12(4):253–68. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 56. Pandey G. Tumor-associated macrophages in solid tumor: friend or foe. Ann Transl Med. 2020;8(16):1027. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 57. Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: N1 versus N2 TAN. Cancer Cell. 2009;16(3):183–94. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 58. Jaillon S, Ponzetta A, Di Mitri D, et al. Neutrophil diversity and plasticity in tumour progression and therapy. Nat Rev Cancer. 2020;20(9):485–503. [ DOI ] [ PubMed ] [ Google Scholar ] 59. Andzinski L, Kasnitz N, Stahnke S, et al. Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human. Int J Cancer. 2016;138(8):1982–93. [ DOI ] [ PubMed ] [ Google Scholar ] 60. Jablonska J, Leschner S, Westphal K, et al. Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model. J Clin Invest. 2010;120(4):1151–64. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 61. Shaul ME, Levy L, Sun J, et al. Tumor-associated neutrophils display a distinct N1 profile following TGFbeta modulation: A transcriptomics analysis of pro- vs. antitumor TANs. Oncoimmunology. 2016;5(11):e1232221. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 62. Grover A, Sanseviero E, Timosenko E, et al. Myeloid-Derived Suppressor Cells: A Propitious Road to Clinic. Cancer Discov. 2021;11(11):2693–706. [ DOI ] [ PubMed ] [ Google Scholar ] 63. Jia K, Chen Y, Xie Y, et al. Multidimensional immune profiling in Gastric Cancer Multiplex Immunohistochemistry Atlas from Peking University Cancer Hospital project informs PD-1/PD-L1 blockade efficacy. Eur J Cancer. 2023;189:112931. [ DOI ] [ PubMed ] [ Google Scholar ] 64. Chen Y, Jia K, Sun Y, et al. Predicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment. Nat Commun. 2022;13(1):4851. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 65. Antuamwine BB, Bosnjakovic R, Hofmann-Vega F, et al. N1 versus N2 and PMN-MDSC: A critical appraisal of current concepts on tumor-associated neutrophils and new directions for human oncology. Immunol Rev. 2023;314(1):250–79. [ DOI ] [ PubMed ] [ Google Scholar ] 66. Shaul ME, Fridlender ZG. Tumour-associated neutrophils in patients with cancer. Nat Rev Clin Oncol. 2019;16(10):601–20. [ DOI ] [ PubMed ] [ Google Scholar ] 67. Zaitsev A, Chelushkin M, Dyikanov D, et al. Precise reconstruction of the TME using bulk RNA-seq and a machine learning algorithm trained on artificial transcriptomes. Cancer Cell. 2022;40(8):879–94. e16. [ DOI ] [ PubMed ] [ Google Scholar ] 68. Zhou SL, Yin D, Hu ZQ, et al. A Positive Feedback Loop Between Cancer Stem-Like Cells and Tumor-Associated Neutrophils Controls Hepatocellular Carcinoma Progression. Hepatology. 2019;70(4):1214–30. [ DOI ] [ PubMed ] [ Google Scholar ] 69. Grossmann Sde M, Teixeira R, Oliveira GC, et al. Xerostomia, hyposalivation and sialadenitis in patients with chronic hepatitis C are not associated with the detection of HCV RNA in saliva or salivary glands. J Clin Pathol. 2010;63(11):1002–7. [ DOI ] [ PubMed ] [ Google Scholar ] 70. Xie P, Yu M, Zhang B, et al. CRKL dictates anti-PD-1 resistance by mediating tumor-associated neutrophil infiltration in hepatocellular carcinoma. J Hepatol. 2024;81(1):93–107. [ DOI ] [ PubMed ] [ Google Scholar ] 71. Piccard H, Muschel RJ, Opdenakker G. On the dual roles and polarized phenotypes of neutrophils in tumor development and progression. Crit Rev Oncol Hematol. 2012;82(3):296–309. [ DOI ] [ PubMed ] [ Google Scholar ] 72. Sionov RV, Fridlender ZG, Granot Z. The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment. Cancer Microenviron. 2015;8(3):125–58. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 73. Houghton AM. The paradox of tumor-associated neutrophils: fueling tumor growth with cytotoxic substances. Cell Cycle. 2010;9(9):1732–7. [ DOI ] [ PubMed ] [ Google Scholar ] 74. El-Benna J, Hurtado-Nedelec M, Marzaioli V, et al. Priming of the neutrophil respiratory burst: role in host defense and inflammation. Immunol Rev. 2016;273(1):180–93. [ DOI ] [ PubMed ] [ Google Scholar ] 75. Ley K, Hoffman HM, Kubes P et al. Neutrophils: New insights and open questions. Sci Immunol 2018;3(30). [ DOI ] [ PubMed ] 76. Mantovani A, Cassatella MA, Costantini C, et al. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol. 2011;11(8):519–31. [ DOI ] [ PubMed ] [ Google Scholar ] 77. McFarlane AJ, Fercoq F, Coffelt SB et al. Neutrophil dynamics in the tumor microenvironment. J Clin Invest 2021;131(6). [ DOI ] [ PMC free article ] [ PubMed ] 78. Furumaya C, Martinez-Sanz P, Bouti P, et al. Plasticity in Pro- and Anti-tumor Activity of Neutrophils: Shifting the Balance. Front Immunol. 2020;11:2100. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 79. Zhang X, Zhang W, Yuan X, et al. Neutrophils in cancer development and progression: Roles, mechanisms, and implications (Review). Int J Oncol. 2016;49(3):857–67. [ DOI ] [ PubMed ] [ Google Scholar ] 80. Catena R, Bhattacharya N, El Rayes T, et al. Bone marrow-derived Gr1 + cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. Cancer Discov. 2013;3(5):578–89. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 81. Finisguerra V, Di Conza G, Di Matteo M, et al. MET is required for the recruitment of anti-tumoural neutrophils. Nature. 2015;522(7556):349–53. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 82. Masucci MT, Minopoli M, Carriero MV. Tumor Associated Neutrophils. Their Role in Tumorigenesis, Metastasis, Prognosis and Therapy. Front Oncol. 2019;9:1146. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 83. Cui C, Chakraborty K, Tang XA, et al. Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis. Cell. 2021;184(12):3163–e7721. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 84. Hirschhorn D, Budhu S, Kraehenbuehl L, et al. T cell immunotherapies engage neutrophils to eliminate tumor antigen escape variants. Cell. 2023;186(7):1432–e4717. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 85. Kalafati L, Kourtzelis I, Schulte-Schrepping J, et al. Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity. Cell. 2020;183(3):771–85. e12. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 86. Kang W, Wang C, Wang M, et al. A key regulator of tumor-associated neutrophils: the CXCR2 chemokine receptor. J Mol Histol. 2024;55(6):1051–61. [ DOI ] [ PubMed ] [ Google Scholar ] 87. Zhou SL, Dai Z, Zhou ZJ, et al. CXCL5 contributes to tumor metastasis and recurrence of intrahepatic cholangiocarcinoma by recruiting infiltrative intratumoral neutrophils. Carcinogenesis. 2014;35(3):597–605. [ DOI ] [ PubMed ] [ Google Scholar ] 88. Deryugina EI, Zajac E, Juncker-Jensen A, et al. Tissue-infiltrating neutrophils constitute the major in vivo source of angiogenesis-inducing MMP-9 in the tumor microenvironment. Neoplasia. 2014;16(10):771–88. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 89. Pan JJ, Xie SZ, Zheng X, et al. Acetyl-CoA metabolic accumulation promotes hepatocellular carcinoma metastasis via enhancing CXCL1-dependent infiltration of tumor-associated neutrophils. Cancer Lett. 2024;592:216903. [ DOI ] [ PubMed ] [ Google Scholar ] 90. Zhou SL, Zhou ZJ, Hu ZQ, et al. Tumor-Associated Neutrophils Recruit Macrophages and T-Regulatory Cells to Promote Progression of Hepatocellular Carcinoma and Resistance to Sorafenib. Gastroenterology. 2016;150(7):1646–e5817. [ DOI ] [ PubMed ] [ Google Scholar ] 91. Yan C, Huo X, Wang S, et al. Stimulation of hepatocarcinogenesis by neutrophils upon induction of oncogenic kras expression in transgenic zebrafish. J Hepatol. 2015;63(2):420–8. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 92. Tazzyman S, Barry ST, Ashton S, et al. Inhibition of neutrophil infiltration into A549 lung tumors in vitro and in vivo using a CXCR2-specific antagonist is associated with reduced tumor growth. Int J Cancer. 2011;129(4):847–58. [ DOI ] [ PubMed ] [ Google Scholar ] 93. Jia X, Wei S, Xiong W. CXCL5/NF-kappaB Pathway as a Therapeutic Target in Hepatocellular Carcinoma Treatment. J Oncol. 2021;2021:9919494. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 94. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9(3):162–74. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 95. Wu X, Chen J, Chen Y, et al. Targeting Deltex E3 Ubiquitin Ligase 2 Inhibits Tumor-associated Neutrophils and Sensitizes Hepatocellular Carcinoma Cells to Immunotherapy. Adv Sci (Weinh). 2025;12(7):e2408233. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 96. Wang P, Xu MH, Xu WX, et al. CXCL9 Overexpression Predicts Better HCC Response to Anti-PD-1 Therapy and Promotes N1 Polarization of Neutrophils. J Hepatocell Carcinoma. 2024;11:787–800. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 97. Qin F, Liu X, Chen J, et al. Anti-TGF-beta attenuates tumor growth via polarization of tumor associated neutrophils towards an anti-tumor phenotype in colorectal cancer. J Cancer. 2020;11(9):2580–92. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 98. He G, Zhang H, Zhou J, et al. Peritumoural neutrophils negatively regulate adaptive immunity via the PD-L1/PD-1 signalling pathway in hepatocellular carcinoma. J Exp Clin Cancer Res. 2015;34:141. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 99. Leslie J, Mackey JBG, Jamieson T, et al. CXCR2 inhibition enables NASH-HCC immunotherapy. Gut. 2022;71(10):2093–106. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 100. Xu W, Zhao Y, Weng J et al. Galectin-4 drives anti-PD-L1/BVZ resistance by regulating metabolic adaptation and tumour-associated neutrophils in hepatocellular carcinoma. Gut 2025. [ DOI ] [ PubMed ] 101. Ning Y, Lei K, Gao X, et al. Targeting neutrophil-driven immunosuppression: A strategy to overcome immune checkpoint inhibitor resistance. Clin Transl Med. 2026;16(1):e70582. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 102. Zhang D, Wu M, Cai Z, et al. Chemotherapeutic Drug Based Metal-Organic Particles for Microvesicle-Mediated Deep Penetration and Programmable pH/NIR/Hypoxia Activated Cancer Photochemotherapy. Adv Sci (Weinh). 2018;5(2):1700648. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 103. Chu D, Dong X, Shi X, et al. Neutrophil-Based Drug Delivery Systems. Adv Mater. 2018;30(22):e1706245. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 104. Wang Y, Zhao Q, Zhao B, et al. Remodeling Tumor-Associated Neutrophils to Enhance Dendritic Cell-Based HCC Neoantigen Nano-Vaccine Efficiency. Adv Sci (Weinh). 2022;9(11):e2105631. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 105. Qiao Q, Liu X, Yang T, et al. Nanomedicine for acute respiratory distress syndrome: The latest application, targeting strategy, and rational design. Acta Pharm Sin B. 2021;11(10):3060–91. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 106. Zhang Y, Guoqiang L, Sun M, et al. Targeting and exploitation of tumor-associated neutrophils to enhance immunotherapy and drug delivery for cancer treatment. Cancer Biol Med. 2020;17(1):32–43. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 107. Yang S, Jia J, Wang F, et al. Targeting neutrophils: Mechanism and advances in cancer therapy. Clin Transl Med. 2024;14(3):e1599. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 108. Brinkmann V, Zychlinsky A. Neutrophil extracellular traps: is immunity the second function of chromatin? J Cell Biol. 2012;198(5):773–83. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 109. Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532–5. [ DOI ] [ PubMed ] [ Google Scholar ] 110. Jorch SK, Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med. 2017;23(3):279–87. [ DOI ] [ PubMed ] [ Google Scholar ] 111. Perez-Figueroa E, Alvarez-Carrasco P, Ortega E, et al. Neutrophils: Many Ways to Die. Front Immunol. 2021;12:631821. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 112. Albrengues J, Shields MA, Ng D, et al. Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science. 2018;361:6409. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 113. Cools-Lartigue J, Spicer J, McDonald B, et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J Clin Invest. 2013;123(8):3446–58. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 114. Cedervall J, Zhang Y, Olsson AK. Tumor-Induced NETosis as a Risk Factor for Metastasis and Organ Failure. Cancer Res. 2016;76(15):4311–5. [ DOI ] [ PubMed ] [ Google Scholar ] 115. Tohme S, Yazdani HO, Al-Khafaji AB, et al. Neutrophil Extracellular Traps Promote the Development and Progression of Liver Metastases after Surgical Stress. Cancer Res. 2016;76(6):1367–80. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 116. Zhu W, Fan C, Dong S, et al. Neutrophil extracellular traps regulating tumorimmunity in hepatocellular carcinoma. Front Immunol. 2023;14:1253964. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 117. Song M, Zhang C, Cheng S, et al. DNA of Neutrophil Extracellular Traps Binds TMCO6 to Impair CD8 + T-cell Immunity in Hepatocellular Carcinoma. Cancer Res. 2024;84(10):1613–29. [ DOI ] [ PubMed ] [ Google Scholar ] 118. Yang LY, Luo Q, Lu L, et al. Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response. J Hematol Oncol. 2020;13(1):3. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 119. Zhan X, Wu R, Kong XH, et al. Elevated neutrophil extracellular traps by HBV-mediated S100A9-TLR4/RAGE-ROS cascade facilitate the growth and metastasis of hepatocellular carcinoma. Cancer Commun (Lond). 2023;43(2):225–45. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 120. van der Windt DJ, Sud V, Zhang H, et al. Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis. Hepatology. 2018;68(4):1347–60. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 121. Wang T, Zhou Y, Zhou Z, et al. Secreted protease PRSS35 suppresses hepatocellular carcinoma by disabling CXCL2-mediated neutrophil extracellular traps. Nat Commun. 2023;14(1):1513. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 122. Yu Y, Zhang C, Dong B, et al. Neutrophil extracellular traps promote immune escape in hepatocellular carcinoma by up-regulating CD73 through Notch2. Cancer Lett. 2024;598:217098. [ DOI ] [ PubMed ] [ Google Scholar ] 123. Jiang ZZ, Peng ZP, Liu XC, et al. Neutrophil extracellular traps induce tumor metastasis through dual effects on cancer and endothelial cells. Oncoimmunology. 2022;11(1):2052418. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 124. Wang Q, Huang Y, Zhu Y, et al. The m6A methyltransferase METTL5 promotes neutrophil extracellular trap network release to regulate hepatocellular carcinoma progression. Cancer Med. 2024;13(7):e7165. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 125. Pan B, Zhang Z, Ye D, et al. PPARalpha suppresses growth of hepatocellular carcinoma in a high-fat diet context by reducing neutrophil extracellular trap release. JHEP Rep. 2025;7(1):101228. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article. Data Availability Statement No datasets were generated or analysed during the current study. Articles from Discover Oncology are provided here courtesy of Springer ACTIONS View on publisher site PDF (2.0 MB) Cite Collections Permalink RESOURCES Similar articles Cited by other articles Links to NCBI Databases Follow NCBI NCBI on X (formerly known as Twitter) NCBI on Facebook NCBI on LinkedIn NCBI on GitHub NCBI RSS feed Connect with NLM NLM on X (formerly known as Twitter) NLM on Facebook NLM on YouTube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov Back to Top

Related documents

• Mechanism of Cancer Induced Neutrophil Differentiation#672811
• Different First-line Immunotherapy for Advancer Hepatocellular Carcinoma: A Prospective Observational Study on Efficacy and Immune Microenvironment#329504
• Identification of telomere-related gene signatures for immune cell infiltration and prognosis in hepatocellular carcinoma.#368069
• Efficacy and Safety of 'Immuncell-LC Group' and 'Non-treatment Group' in Nexavar Treated Patients for Advanced HCC#1089033
• In vitro 3D liver tumor microenvironment models for immune cell therapy optimization#1175220