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. 2025 Jan 16;24:22. doi: 10.1186/s12943-025-02228-7

Bidirectional role of neutrophils in tumor development

Haoxin Luyang 1,2, Feng Zeng 2, Yan Lei 3, Qian He 4, Yanhong Zhou 2,✉, Juan Xu 1,✉
PMCID: PMC11737241  PMID: 39819428

Abstract

Neutrophils, traditionally considered as non-specific components of the innate immune system, have garnered considerable research interest due to their dual roles in both promoting and inhibiting tumor progression. This paper seeks to clarify the specific mechanisms by which neutrophils play a bidirectional role in tumor immunity and the factors that influence these roles. By conducting a comprehensive analysis and synthesis of a vast array of relevant literature, it has become evident that neutrophils can influence tumor development and invasive migration through various mechanisms, thereby exerting their anti-tumor effects. Conversely, they can also facilitate tumorigenesis and proliferation, as well as affect the normal physiological functions of other immune cells, thus exerting pro-tumor effects. Moreover, neutrophils are influenced by tumor cells and their unique microenvironment, which in turn affects their heterogeneity and plasticity. Neutrophils interact with tumor cells to regulate various aspects of their life activities precisely. This paper also identifies unresolved issues in the research concerning the bidirectional role of neutrophils in tumorigenesis and tumor development, offering new opportunities and challenges for advancing our understanding. This, in turn, can aid in the proper application of these insights to clinical treatment strategies.

Keywords: Neutrophils, Tumor immunity, Anti-tumor effects, Tumor-promoting effects, Bidirectional role

Introduction

Neutrophils are the most abundant type of white blood cells in the human circulatory system, originating from myeloid stem cells in the bone marrow. They have a short half-life and a rapid renewal rate, with an average lifespan of 2–3 days. Constituting the largest proportion of white blood cells in the bloodstream, neutrophils account for 60-70% of the total count [1]. Unlike other immune cells, neutrophils do not express specific antigen receptors; instead, they primarily recognize, undergo chemotaxis, and non-specifically eliminate pathogenic microorganisms as part of the innate immune response. As phagocytes, neutrophils release lytic enzymes from their granules and produce reactive oxygen intermediates, both of which possess antimicrobial properties [2]. These functions are crucial for fundamental life activities, including infection, trauma, stress, and inflammation. Although neutrophils were once considered terminally differentiated cells, recent observations in tumor patients have challenged this traditional view. Scholars have discovered that neutrophils form a heterogeneous population with varying morphologies, activation states, and cell surface markers, depending on their environment [3]. This heterogeneity suggests that neutrophils can exhibit diverse functional patterns based on their surroundings [4, 5].

Once, it was commonly accepted that neutrophils played a non-specific anti-tumor role in tumor immunity. However, recent research has unveiled a more nuanced and multifaceted role for neutrophils [6]. As our understanding of neutrophils deepens, it has become clear that they exhibit various phenotypes and play distinct roles depending on the type of cancer they encounter. Fridlender and his colleagues have identified two fundamental neutrophil populations, termed the N1 and N2 types [7], which respond differently to local microenvironmental cues [8]. This insight has significantly advanced our comprehension of tumor immunity, encouraging researchers to reassess their view of neutrophils as “old friends” with a fresh perspective [9]. In this review, we will explore the roles of neutrophils through the lens of the N1 and N2 populations. The N1 population encompasses non-specific neutrophils that are part of the innate immune system [10], while the N2 population, referred to as “new friends,” includes tumorigenic neutrophils in tumor immunity, such as tumor-associated neutrophils (TANs) that can promote angiogenesis, metastasis, and immunosuppression [11]. It is well-established that TANs are typically linked to poor prognosis in most human cancers [12]. However, they may also display anti-tumorigenic effects in early-stage cancers or when TGF-β signaling is inhibited [13]. Thus, neutrophils exert a bidirectional influence on tumor immunity, with effects that can vary between different subpopulations, as well as at distinct stages of tumor progression and across different cancer types.

Subpopulations of neutrophils and their functional characteristics

As research into neutrophils continues to expand, it has become evident that these cells display a variety of subtypes and functions within the realm of cancer immunity. As previously noted, neutrophils exhibit distinct polarization phenotypes in response to the dynamic nature of the tumor microenvironment, specifically the anti-tumorigenic (N1) and pro-tumorigenic (N2) phenotypes [6]. The N1 and N2 subtypes have been characterized based on their morphology, granule density, cell surface markers, cytokine or chemokine expression, and functional properties [14]. It is now well recognized that neutrophils participate in both the initiation and progression of tumors. N1 neutrophils can utilize reactive oxygen species (ROS) and the tumor necrosis factor TNF-α to combat tumor cells [15], whereas N2 neutrophils can suppress T-cell activation and promote cancer development through various mechanisms [16].

In fact, the density of neutrophils in tumor tissues can vary among different populations. High-density neutrophils (HDNs) and low-density neutrophils (LDNs) are two distinct types of human circulating neutrophils that can be differentiated using a discontinuous density gradient to separate leukocytes from whole bloodstream [17]. This density gradient differentiation may be attributed to differences in activation and degranulation states, as well as varying levels of maturation [18]. The acquisition of cytoplasmic granules, which leads to an increase in cell density, is a critical terminal event in the maturation of neutrophils [19]. Density gradient centrifugation is a technique that can be employed to separate neutrophils based on their maturity stages. Mature neutrophils, whose cytoplasm is rich in granulocyte particles, are categorized as HDNs. In contrast, LDNs are composed of two parts: one part consists of immature neutrophils that lack cytoplasmic granules [20], and the other part consists of mature neutrophils that have undergone degranulation. Scholars have found that TGF-β inhibits neutrophil H2O2 production in response to phorbol myristate acetate (PMA), a PKC receptor-independent neutrophil activator, which leads to the degranulation of mature neutrophils induced by lipopolysaccharide [21].

Research has revealed a significant association between neutrophil populations and cancer progression. Specifically, it has been observed that the low-density neutrophil (LDN) population expands with tumor growth in both mice and cancer patients [22]. Studies have further demonstrated that LDNs and HDNs in mice exert opposing effects on cancer progression. While LDNs exhibit minimal cytotoxicity towards tumor cells, HDNs are highly cytotoxic, with the precise mechanisms to be detailed in the subsequent sections. However, there remains a scarcity of definitive cell surface markers that can distinguish between LDNs and HDNs subpopulations. Interestingly, LDNs and HDNs can interconvert under certain conditions [21, 23], highlighting the dynamic nature of these cells. Historically, CD16 has been employed as a marker for mature neutrophils, and more recently, CD10 has also been identified as a marker for mature neutrophils [24]. Identifying the precise molecular distinctions between these two subpopulations is a critical challenge that researchers are actively addressing. Uncovering these differences could significantly enhance the efficiency and accuracy of neutrophil-related cancer research.

Anti-tumor effects of neutrophils

Neutrophils inhibit tumorigenesis and growth by exerting tumor cytotoxicity

The challenge of selectively targeting cancer cells without harming normal cells has long perplexed scientists, given the similarities between cancer and host cells. Achieving selective tumor immunity is crucial as it can potentially inhibit tumorigenesis at its root or improve the prognosis of cancer patients by curbing the growth and proliferation of tumor cells [25]. The mechanisms of cell killing are diverse and include, but are not limited to, the induction of apoptosis, ferroptosis [26], oxidative damage, and indirect effects such as mediating the immune system to enhance antibody-dependent cellular cytotoxicity (ADCC) and activating T cells. These multifaceted mechanisms work in concert to eliminate tumor cells.

The BCG treatment for bladder cancer has been one of the most promising immunotherapies for the disease, and researchers have found that neutrophils play a crucial role in the mechanism by which BCG works on bladder cancer. When stimulated by BCG cells, neutrophils can release tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which plays an important role in inducing tumor cell apoptosis. Furthermore, neutrophils stimulated by BCG can release neutrophil extracellular traps (NETs), substances that contain DNA, elastase, and histones [27]. Through these mechanisms, the BCG-mediated anti-tumor immune response induces neutrophils to kill tumor cells via phagocytosis and degranulation.

Mouse neutrophils have the capability to release catalytic neutrophil elastase (ELANE), an enzyme that can effectively kill various types of cancer cells while sparing non-cancerous cells. The hydrolysis of the ELANE protein leads to the release of the CD95 death domain, which then interacts with histone H1 isoforms to selectively target and eliminate cancer cells [28]. This selective immune mechanism significantly enhances the specificity of anti-tumor effects, boosts the efficiency of tumor cell killing, and minimizes damage to normal tissues and the side effects associated with non-selective cancer immunity. Moreover, ELANE not only slows the growth of primary tumors but also stimulates CD8 + T cell-mediated responses in vitro, which can attack distant metastatic tumors. Interestingly, it has been observed that viral infections can enhance neutrophil-T cell interactions, thereby strengthening cellular immunity against tumors [29]. These findings underscore the potential of neutrophils in cancer immunotherapy.

Neutrophils not only weaken tumorigenesis but also play a role in inhibiting tumor growth. Some researchers have pretreated mice with β-glucan, a fungus-derived immunophenotypic agonist, and observed a reduction in tumor growth [30]. This anti-tumor activity of neutrophils can be further enhanced through the activation of cell-autonomous signals. For instance, β-glucan induction trains the immune system in mice, enhancing its anti-tumor effects. This training immunity mechanism is linked to the reprogramming of neutrophils towards an anti-tumor phenotype, with neutrophils suppressing tumor development in a reactive oxygen species (ROS)-dependent manner in β-glucan-trained mice [31]. In certain scenarios, neutrophils can also be recruited through a series of signals to limit tumorigenesis, growth, and proliferation [32]. The hypoxic conditions in tumor tissues induce the expression of C-X-C ligands (CXCL1, CXCL2, and CXCL5), which attract large numbers of the previously mentioned N1-type anti-tumor neutrophil aggregates (Fig. 1A). Subsequently, endothelium-derived tumor necrosis factor (TNF) up-regulates the expression of MET (the hepatocyte growth factor receptor) on neutrophil membranes, leading to the production of inducible nitric oxide synthase (iNOS) that exerts a cytotoxic effect on cancer cells [33].

Fig. 1.

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Anti-tumor effects of neutrophils

Neutrophils have long been recognized as key players in mediating antibody-dependent cellular cytotoxicity (ADCC). They are essential and sufficient for anti-tumor IgG to eliminate mouse subcutaneous xenograft tumors through a Syk (spleen tyrosine kinase)-dependent induction of Fcγ receptors (FcγR) (Fig. 1B) [34]. The intricate interplay among neutrophils and T cells in anti-tumor immunity has been extensively studied by scientists worldwide. A pivotal study showed that TANs can stimulate T cell proliferation and the release of interferon IFN-γ in early-stage human lung cancer [35]. The crosstalk between TANs and activated T cells leads to a significant increase in the expression of co-stimulatory molecules on the surface of neutrophils. This interaction enhances the T cell response, creating a positive feedback loop that stimulates the anti-tumor response of T cells [30]. Vijayashree Mysore and colleagues discovered that FcγR-mediated endocytosis facilitates the transition of neutrophils into antigen-presenting cells (APCs), which induces CD8 + T cell-dependent anti-tumor immunity in mouse models [36]. Additionally, TANs can enhance the secretion of IL-12 by macrophages in some human tumors, thereby shifting the polarization of a subset of unconventional αβ T cells (UTCαβ) towards type 1 phenotype (Fig. 1C) [37]. This shift promotes the anti-tumor effects of T cells.

Neutrophils inhibit tumor invasive migration through the combined action of multiple mechanisms such as secretion of reactive oxygen species and induction of ferroptosis

In today’s clinical cancer care, the severe multi-organ functional damage or even patient mortality resulting from distant metastasis and tumor invasion poses one of the most significant challenges for clinicians. Patients with extensive metastasis typically have a poor prognosis. Tumor invasion and migration is a complex, multistep process that includes intravasation, survival in the circulation, extravasation, colonization, and survival in distant tissues [22]. The overall efficiency of tumor metastasis is remarkably low due to the intricate nature of this process and the complexity of each step. Despite a large number of cells disseminating from the primary tumor, only a small fraction of which can form metastases [38]. This understanding has spurred the development of innovative approaches to cancer treatment, offering new perspectives on inhibiting metastasis and improving the prognosis for cancer patients. These approaches focus on manipulating the challenging conditions necessary for tumor invasion and migration. Notably, the potential for neutrophils to inhibit metastasis has attracted considerable interest among researchers.

Zvi Granot and his colleagues have demonstrated that tumor-educated neutrophils (TENs) inhibit lung metastasis through the production of hydrogen peroxide (H2O2). They have shown that tumor-secreted CCL2 is the key mediator of optimal anti-metastatic activity, particularly when neutrophils are stimulated by granulocyte colony-stimulating factor (G-CSF) (Fig. 1D) [39]. Neutrophils arrive at pre-metastatic sites earlier than detectable metastatic tumor cells and are activated by chemokines such as CCL2/5, which are secreted by the primary tumor [40]. These neutrophils are not inhibited by tumor-secreted TGF-β and acquire an anti-tumorigenic “N1” phenotype, enabling them to kill metastatic cells. Indeed, both CCL2 secreted by the primary tumor and the later mentioned IL-17 are double-edged swords. In lung tissues with low TGF-β activity, as discussed in this section, CCL2 induces a neutrophil-mediated anti-metastatic response. In contrast, in primary tumors with high TGF-β activity where neutrophils are suppressed, CCL2 acts as a tumor promoter [41]. This duality will be further discussed in the section on the pro-tumorigenic effects of neutrophils.

Radiation therapy (RT) has been found to induce sterile inflammation and a rapid infiltration of neutrophils into the tumor, which exhibit increased production of reactive oxygen species (ROS) [42]. This surge in ROS acts on tumor cells, inducing apoptosis. Additionally, neutrophil-derived hydrogen peroxide (H2O2) induces Ca2 + influx into tumor cells, efficiently killing them. This process is mediated by TRPM2, an H2O2-sensitive Ca2 + osmotic channel [43]. Through this mechanism, neutrophils encapsulated in the metastatic ecotope inhibit the metastatic potential of tumor cells [44]. Furthermore, neutrophils can exert cancer cell-killing effects through the release of nitric oxide (NO). The HGF/MET signaling pathway plays a key role in promoting the release of NO from neutrophils, resulting in oxidatively damaging cytotoxic effects on cancer cells (Fig. 1E) [32]. Neutrophils also promote iron-mediated aggregation of lipid peroxides in glioblastoma cells by transferring particles loaded with myeloperoxidase (MPO) to tumor cells, thereby promoting ferroptosis (Fig. 1F) [45].

The addition of neutrophils has been shown to play a significant role in disrupting the entire process of tumor cell development [46]. Moreover, they enhance the intensity and cytotoxicity of various immune and non-immune cells, as well as the cytokines these cells produce within the tumor microenvironment, against tumor cells [47]. Therefore, a deeper understanding of the anti-tumor activities of neutrophils and their mechanisms could pave the way for innovative approaches in cancer therapy (Fig. 1).

(A) The hypoxic environment of tumor tissue can promote the release of chemokines CXCL1, CXCL2, and CXCL5 into the bloodstream, thereby facilitating the recruitment of neutrophils from the bloodstream to the tumor microenvironment and cascading to amplify the anti-tumor effects of neutrophils. (B) FcγR can induce CD8 + T cell-dependent anti-tumor immunity by promoting the transformation of neutrophils into antigen-presenting cells (APCs) through its mediated endocytosis. Neutrophils can also exert cancer cell-killing effects by releasing nitric oxide (NO). (C) TANs promote the secretion of IL-12 by macrophages in tumor tissue, thereby redirecting the polarization of a subset of unconventional αβ T cells (UTCαβ) towards type 1, which enhances the anti-tumor effect of T cells. (D) TANs inhibit lung metastasis by producing H2O2. The chemokine ligand CCL2, secreted by tumors, is a key mediator that stimulates the anti-metastatic effect of neutrophils. It binds to its specific receptor CCR2 on the cell membrane of neutrophils, thereby promoting the release of hydrogen peroxide (H2O2) and inhibiting tumor metastasis. (E) The MET signaling pathway plays a key role in promoting the release of NO by neutrophils, which exerts oxidative cytotoxic effects on cancer cells through TNF-α and hepatocyte growth factor (HGF). (F) Neutrophils promote iron-mediated aggregation of lipid peroxides in glioblastoma cells by transferring particles loaded with myeloperoxidase (MPO) to tumor cells, thereby inducing ferroptosis and promoting cell necrosis.

Tumor-promoting effects of neutrophils

Neutrophil-mediated tumorigenesis

In recent years, the role of inflammatory responses in tumorigenesis, in addition to classical mutation-induced mechanisms, has garnered increasing attention from scholars as a significant pathway to cancer development. Neutrophils, which are pivotal players in the inflammatory response, have a substantial influence on this process. Their impact on tumorigenesis is primarily indirect, mediated through their role in shaping the inflammatory environment [48].

The precise role of neutrophils in promoting tumorigenesis through inflammation remains incompletely understood. Some scholars have experimentally speculated that neutrophil-derived elastase and the immunosuppressive properties of neutrophils may be associated with the initiation of tumors, yet the specific mechanisms await further clarification. Additionally, reactive oxygen species (ROS), reactive nitrogen species (RNS), and angiogenic factors like MMP9, which are produced in large quantities during cytokine storms and circulate in the bloodstream, may also serve as significant mediators in tumor initiation [49]. In forthcoming research, genetically engineered mouse tumor models are expected to play a crucial role in advancing the field of cancer-related neutrophil biology [50]. These models will facilitate the tracking of neutrophil production and chemotaxis, as well as the behavior of their derivatives, from the very onset of tumorigenesis [51]. Such studies have the potential to uncover the intricate interplay between neutrophils in inflammatory contexts and the process of tumorigenesis (Fig. 2A).

Fig. 2.

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Tumor-promoting effects of neutrophils

Neutrophil extracellular traps (NETs) are released during neutrophil activation. Composed of DNA and modified proteins, NETs form extracellular fibers that trap and kill extracellular pathogens, and they also play a variety of roles in cancer-related inflammation. It has been reported that NETs drive endothelium-mesenchymal transformation (EMT) [52], which plays an important role in tumorigenesis. The dismantling of NETs reduces stromal activation and tumor growth [53]. Recently, it has been shown that IL-8/CXCL8 mediates a positive feedback loop connecting NET formation and colorectal cancer liver metastasis [54]. In summary, NETs play a significant role in cancer initiation, metastasis formation and spread, and cancer-related thrombosis. It is worth noting that NETs are not limited to a simple promoting effect on cancer; in fact, they play a comprehensive role in the bidirectional regulation of tumor and anti-tumor responses within tumor immunity [55]. The role of NETs in tumor angiogenesis is discussed in the following section.

Neutrophils promote the proliferation of tumor cells

Several specific molecules can induce epithelial injury, leading to pro-tumorigenic inflammation. Injured epithelial cells recruit neutrophils and rapidly release large quantities of prostaglandin E2 (PGE2), which promotes tumor growth [38]. Additionally, tumor necrosis factor (TNF-α) can regulate tumor growth promotion by inducing CD4 + T cells to activate the production of interleukin (IL-17), thereby mediating crosstalk among neutrophils [56]. Beyond tumor initiation, neutrophils also contribute to tumor growth by converting senescent cancer cells into proliferating ones through the action of interleukin-1 receptor antagonists (IL-1RA) [57] (Fig. 2B).

Tumor cell proliferation can be directly stimulated by the transfer of neutrophil elastase (NE) to cancer cells, which leads to the degradation of insulin receptor substrate 1 (IRS1) and subsequently activates the PI3K signaling pathway [58]. Neutrophils can express inducible nitric oxide synthase (iNOS) or arginase 1 (ARG1), which inhibit CD8 + T cell-mediated anti-tumor immune responses, thereby suppressing the immune system’s interference with tumor proliferation. This immunosuppressive effect can also be mediated by alterations in transforming growth factor-β (TGF-β) signaling [59]. Furthermore, neutrophils contribute to the remodeling of the extracellular matrix (ECM) by producing matrix metalloproteinase 9 (MMP9), which triggers the substantial release of vascular endothelial growth factor A (VEGFA) [60]. This release can induce angiogenesis, supplying the nutrients and energy necessary for the unlimited proliferation of tumor cells, and thus promotes tumor growth [61] (Fig. 2C). The angiopoietin (ANGPT) family is another important class of angiogenic factors. Aldabbous and his collaborators found that NET-induced angiogenesis was induced by prolonged incubation in both a 2-dimensional matrigel tube formation assay and a 3-dimensional spheroid sprouting assay [62]. Sirois and collaborators reported that both ANGPT1 and ANGPT2 induce human neutrophils to synthesize endothelial platelet-activating factor (PAF), which promotes NET formation and thereby increases capillary tube length, loop number, and tubule area [63].

(A) When normal epithelial tissue is damaged, neutrophils can release reactive oxygen species (ROS), nitric oxide synthase (NOS), and proteases, which promote the inflammatory response in epithelial tissue. This inflammation can lead to the transformation of normal epithelial cells into tumor cells. (B) Neutrophils promote tumor growth through two main mechanisms. Firstly, they induce CD4 + T cells to produce interleukin-17 (IL-17) through the action of tumor necrosis factor α (TNF-α), which mediates crosstalk between neutrophils and regulates tumor growth. Secondly, they convert senescent cancer cells into proliferating ones by secreting IL-1 receptor antagonists (IL-1RA), thereby promoting tumor growth. (C) Neutrophil elastase (NE), when transferred to cancer cells, leads to the degradation of insulin receptor substrate 1 (IRS1) and the activation of the PI3K signaling pathway, directly stimulating tumor cell proliferation. Additionally, neutrophils can induce angiogenesis by directly producing the secreted protein BV8 or indirectly producing matrix metalloproteinase 9 (MMP9), which activates the release of vascular endothelial growth factor A (VEGFA). This leads to the formation of new blood vessels that supply the nutrients and energy required for the unlimited proliferation of tumor cells, thus promoting tumor growth.

Neutrophil-induced apoptosis of CD8 + T cells mediates tumor’s immune escape

In recent years, there has been a growing interest in characterizing the interactions between TANs and other tumor-infiltrating immune cells, as well as understanding their impact on tumor progression. Among all these mechanisms, the interaction between the anti-tumor “workhorse” CD8 + T cells and TANs particularly interests us. Many scholars have focused on how tumor cells influence TANs progression by down-regulating the major histocompatibility complex (MHC) and increasing the expression of immune checkpoint ligands, such as programmed death ligand 1/2 (PD-L1/2), ITIM structural domains (TIGIT), T cell immunoglobulin and mucin structural domain 3 (TIM-3). Additionally, they examine the role of transforming growth factor (TGF-β) and interleukins (IL) in upregulating T cell depletion for immune evasion by tumor cells [64]. In contrast, the apoptosis-inducing effect of neutrophils on CD8 + T cells has received less attention. As previously mentioned, the primary pathways by which neutrophils kill target cells include the release of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) and singlet oxygen (1O2) (produced via the activation of the NADPH oxidase complex), and the production of NO (following the induction of nitric oxide synthase). Michaeli et al. have discovered that while blockers of the oxidase complex can inhibit the production of 1O2, H2O2, and hypochlorous acid (HOCl), they do not prevent CD8 + T cell apoptosis. However, when iNOS inhibitors were introduced, there was a significant inhibition of T cell apoptosis, with the inhibition of apoptosis being seven times more effective [65]. This suggests that TANs primarily induce T cell apoptosis through the production of NO, thereby facilitating the immune escape of tumor cells.

Several studies have demonstrated that granulocytes can influence target cells either through direct cell-to-cell contact or via the secretion of soluble factors, such as cytokines. Some researchers have utilized a transwell assay system to co-culture TANs with CD8 + T cells, which prevents any physical contact between the two cell types while allowing soluble factors to diffuse between them [66]. Notably, apoptosis was significantly reduced when cell-to-cell contact was blocked, yet this blocking did not affect the levels of nitric oxide (NO) production. Although TANs can induce CD8 + T cell activation through crosstalk and have been shown to preferentially promote apoptosis in non-activated T cells (CD8 + CD69- T cells) [67], these findings suggest that TANs may stimulate NO production in CD8 + T cells through a paracrine, cytokine-dependent mechanism that is independent of physical contact. However, the completion of apoptosis itself requires close contact between TANs and CD8 + T cells, involving a contact-dependent induction of apoptosis mediated by tumor necrosis factor-α (TNF-α) and NO (Fig. 3A and B).

Fig. 3.

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Neutrophils induce apoptosis of CD8 + T cells

(A) TANs promote the production and release of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) by secreting tumor necrosis factor α (TNF-α). This process facilitates direct contact between CD8 + T cells and TANs. (B) The close contact between TANs and CD8 + T cells can trigger apoptosis in CD8 + T cells, thereby enabling immune evasion by tumor cells. This is a contact-dependent induction of apoptosis that is mediated by TNF-α and NO.

In summary, neutrophils, as pivotal regulators of the immune system, exhibit seemingly contradictory roles in cancer, encompassing both pro-tumorigenic and anti-tumorigenic functions. The anti-tumorigenic roles have been discussed in the previous section, while this section primarily focuses on the pro-tumorigenic roles. Specifically, N2-type neutrophils positively influence the entire life span of tumor cells, from ontogenesis to growth, proliferation, and metastasis [68]. Beyond their regulatory effects on T cells, neutrophils also interact with a variety of other immune cells, including B cells and macrophages [69], to exert immunomodulatory effects on tumors. It is important to recognize that not only the neutrophils are capable of promoting or inhibiting tumor cell activity, the tumor cells and their microenvironment also play a role in inducing and differentiating neutrophil subpopulations, thereby affecting multiple aspects of neutrophil life activities [70]. In the following section, we will shift our focus from neutrophils to tumor tissues to explore the impact of the tumor microenvironment on neutrophil behavior and function.

Effect of tumor cells on neutrophils in the tumor microenvironment and its mechanism

Effect of tumor cells on neutrophil heterogeneity

Hematopoietic stem cells (HSCs) in the hypoxic microenvironment of the bone marrow can exit quiescence for self-renewal and differentiation, leading to irregular division rates and differentiation directions associated with varying levels of mitochondrial abundance. According to Papa et al., stem cells with higher mitochondrial content will differentiate, giving rise to a hematopoietic cell lineage, such as neutrophils [71], while those with lower mitochondrial content will re-enter quiescence. The ability of HSCs to maintain a low mitochondrial pool is considered a marker of their stemness. Tumor cells can sculpt their local microenvironment to suit their specific metabolic needs, favoring their growth and proliferation. Besides consuming most of the glucose in the tumor microenvironment through glycolysis, tumor cells also increase glutamine metabolism. Consequently, it is not surprising that glutamine levels in the tumor microenvironment (TME) are often low [72]. However, a seminal article challenged the importance of glutamine in tumor metabolism by demonstrating that glutamine consumption did not increase and remained relatively low in an in vivo mouse lung cancer model [73]. Such contradictory results highlight the heterogeneity and plasticity of tumor cell metabolism. The varying mitochondrial abundance in different tumor microenvironments and its direct influence on the levels of glycolysis and glutamine metabolism may contribute to the “customized” shaping of many immune cells within the TME, as represented by neutrophils. Thus, the heterogeneity of neutrophils observed by scholars can be explained by these factors.

Woodin and colleagues recently discovered that neutrophils can migrate retrogradely back into the circulatory system and identified junctional adhesion molecule C (JAM-C) as a key regulator of oriented transendothelial migration (TEM) [74]. Retrograde transendothelial migration (rTEM) appears to contribute to the spread of systemic inflammation. The phenomenon of rTEM also raises the question of whether neutrophils returning from different environments exhibit phenotypic and metabolic changes, contributing to the heterogeneity in the circulating neutrophil pools of both healthy and non-healthy individuals [75]. Although neutrophils can remain homogeneous within the same tissue or organ, the mixing and repooling of neutrophils from different tissues or organs can result in heterogeneity within concentrated tissue regions, such as tumor tissue. Another report describes the role of exogenous glutamine in neutrophil chemotaxis. In the absence of glutamine, neutrophil migration was enhanced, suggesting that a decrease in glutamine concentration in the tumor microenvironment promotes neutrophil migration to the tumor site [76]. Based on this observation, we can deduce that the glutamine deficiency in the tumor microenvironment, due to competitive uptake by tumor cells, facilitates neutrophil retrograde transendothelial migration. This may significantly contribute to the intriguing phenomenon where neutrophils transition from a homogeneous to a more plastic and heterogeneous state following the competitive acquisition of glutamine by tumor cells.

Effect of tumor cells on neutrophil polarization

The complex interactions of TANs with various aspects of tumor cells have been extensively detailed in previous sections. However, the specific steps involved in the polarization process that transform conventional neutrophils into TANs, which are specific to the tumor microenvironment, have not been fully elucidated. This section will therefore focus on illustrating the steps of neutrophil polarization. In the local tumor microenvironment and distant organs, immune cells and their mediators are known to facilitate metastasis formation. Nevertheless, the precise control of metastasis by tumor-induced systemic inflammation and the mechanisms that regulate this inflammation are not well understood [77]. Some investigators have demonstrated that IL-1β induces IL-17 expression in γδ T cells, leading to a systemic, G-CSF-dependent expansion and polarization of neutrophils in mice [78]. Furthermore, researchers have shown that IL-17 acts upstream of G-CSF, suggesting a regulatory loop between these two factors. Tumor-induced neutrophils acquire the ability to suppress cytotoxic CD8 + T lymphocytes, which in turn limits the establishment of metastasis. The depletion of γδ T cells prevents the accumulation of IL-17 or G-CSF and downregulates the T cell suppressive phenotype of neutrophils. Moreover, the absence of γδ T cells or neutrophils significantly reduces lung and lymph node metastasis without affecting primary tumor progression [4]. These findings suggest that targeting the novel tumor-triggered domino effect within the immune system, specifically the γδ T cell-IL-17-neutrophil axis, could be a promising strategy for suppressing metastatic disease (Fig. 4A and B).

Fig. 4.

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Tumor cells mediate the polarization of neutrophils

(A) Tumor cells stimulate the release of more interleukin-17 (IL-17) from γδ T cells by producing interleukin-1β (IL-1β). IL-17 acts as an upstream factor for granulocyte colony-stimulating factor (G-CSF). (B) The production of G-CSF, in turn, promotes the polarization of non-specific neutrophils, leading to the development of TANs. This process shapes the tumor immune activity of neutrophils, influencing their role within the tumor microenvironment.

The role of tumor cells in the recruitment of neutrophils to the tumor microenvironment

The dynamic changes in cell metabolism and cytokine secretion within the tumor microenvironment can limit the functionality of various immune cells. These cells often struggle to adapt to the significant shifts of the tumor microenvironment, which is why the recruitment of immune cells and the amplification of their immune effects through a cascade are particularly crucial [79]. Studies have shown that neutrophils are actively recruited into the tumor microenvironment, following a chemotactic gradient composed of multiple tumor-secreted factors [80]. They infiltrate tissues in response to specific chemokines, such as CXCL1, CXCL2, TNF-α, and IFN-γ [81]. Cell adhesion molecules on the surface of TANs, like CD11b, as well as those on vascular endothelial cells, such as selectins, ICAM-1, and PECAM-1, play pivotal roles in neutrophil rolling, adhesion, and migration from the bloodstream to the tumor site [82]. The chemokine receptors CXCR1 and CXCR2, expressed by TANs, are important for their recruitment, as they bind to tumor-secreted chemokines including CXCL1, CXCL2, CXCL5, CXCL6, and CXCL8. Tumors, by expressing high levels of these chemokines, can disrupt the dynamic homeostasis of neutrophils in the bone marrow and promote their release into the bloodstream, sometimes in early, immature forms. In human cancers, the IL8/CXCL8 pathway is recognized as one of the most potent neutrophil recruitment pathways within the tumor microenvironment.

Clinical potential of neutrophil therapy and prognosis

More and more evidences suggest that TANs can be manipulated to exhibit more cytotoxic phenotypes, raising the possibility that TANs could represent a new target for cancer immunotherapy [83, 84]. It remains unclear whether TANs in patients can be therapeutically manipulated with precision and whether such manipulations could facilitate a phenotypic shift in TANs from tumor-promoting to anti-tumorigenic [85]. Additionally, it is yet to be determined whether tumor immunity could be enhanced through direct secretory substances and exosomes [86]. Undoubtedly, the inhibition of pro-tumor neutrophil activities coupled with the enhancement of their anti-tumor functions is a promising strategy in oncological therapy. This dual approach could pave the way for improving cancer patient outcomes.

Before it was demonstrated that TGF-β could regulate the polarization of neutrophils toward a tumor-promoting phenotype, there were numerous trials aimed at impeding tumor development by blocking TGF-β [87]. These trials provided valuable insights for tumor therapy. However, due to TGF-β’s involvement in many physiological pathways, targeting TGF-β has been challenging because of its significant side effects on other normal biochemical processes. Currently, new strategies and molecules that target TGF-β or its receptors are undergoing clinical trials [88]. Some scientists have proposed that cancer could be treated by inducing a process of antibody-dependent cell-mediated cytotoxicity (ADCC). The binding of monoclonal antibodies to tumor cells may activate various immune cell types, ultimately leading to tumor cell death. Neutrophils, similar to macrophages [89] and NK cells [90], express a variety of Fc receptors, making them potentially important target cells for therapeutic ADCC [91]. The ADCC pathway has shown promise for the treatment of certain cancers, such as head and neck squamous cell carcinoma (HNSCC), colon cancer, and HER2-positive breast cancer [92]. A recent study using the human breast cancer cell line SK-BR-3 demonstrated that neutrophils isolated from healthy volunteers could promote autophagy to induce tumor cell death [93]. Researchers at Fudan University recently discovered that extreme hypoxia in the tumor microenvironment can cause neutrophils to release neutrophil extracellular traps (NETs), which are composed of decondensed chromatin DNA, histones, myeloperoxidase (MPO), and neutrophil elastase (NE) [94]. As a double-edged sword of innate immunity, NETs chronically mediate inflammatory and tumor immunity, maintaining phagocytic activity and the release of cytokines such as G-CSF and TNF-α [95]. Targeting NETs could potentially achieve vascular remodeling of tumor tissues and improve the prognosis of tumor patients to some extent [96]. Similarly, many anti-cancer treatments can be mechanistically studied using clinically relevant mouse tumor models. While there are no specific antibodies targeting unique NET epitopes at present, alternative NET biomarkers have been identified in various malignancies [97]. These biomarkers include circulating free DNA (cfDNA), levels of NET-associated proteins such as neutrophil elastase (NE) and myeloperoxidase (MPO), nucleosomes, and the specific marker circulating citrullinated histone H3 (H3Cit). The combined detection of circulating MPO/DNA or NE/DNA complexes along with plasma H3Cit levels is more specific than assessing cfDNA alone [98]. It is believed that the outcomes of these studies can help us understand the impact of neutrophils on the effectiveness of anti-cancer treatments.

Chemotherapy-induced neutropenia is a critical factor in determining the duration and dosage of cancer treatment, as neutrophil counts during therapy are indicative of the treatment’s intensity. A reduced neutrophil count may suggest an inadequate chemotherapy dose or insufficient tumor cell killing, thereby significantly impacting the prognosis of cancer patients undergoing chemotherapy. Research has indicated that neutropenia following chemotherapy can be mitigated by administering recombinant G-CSF (for example, fexofenadine) [99]. Intriguingly, recent evaluations of neutrophil activation markers have revealed that GM-CSF activation of neutrophils in neuroblastoma patients correlates with improved prognosis after immunotherapy with anti-GD2 monoclonal antibodies [100]. In contemporary oncology, the use of GM-CSF-activated neutrophils is also linked to better outcomes following anti-GD2 monoclonal antibody immunotherapy [100]. The application of macrophage-associated biologics in tumor treatment is on the rise, yet resistance to these therapies, leading to poor prognoses, is emerging [101]. Given the intricate interactions between neutrophils and macrophages [102], neutrophils may play a role in overcoming resistance to macrophage-targeted therapies [1]. Indeed, in RIP1-Tag2 pancreatic and MMTV-PyMT mammary tumor mouse models, neutrophils have been shown to mediate resistance to the anti-angiogenic drug sorafenib, especially when macrophages are blocked [103]. This suggests that targeting one myeloid cell population might require additional targeting of another to counteract therapeutic resistance and enhance prognosis. A recent study from Jiangsu University proposed a genetic engineering approach to modify neutrophils for targeted drug delivery in tumor therapy [104]. This highlights the promising potential of neutrophils in improving cancer patient prognosis, a field that has garnered the attention of scientists globally.

Problems and prospects

Accumulating evidence from basic medical research suggests that neutrophils play bidirectional roles in cancer. Therefore, strategies should be developed to specifically disrupt the pro-tumorigenic effects of neutrophils while restoring their anti-tumorigenic functions. Before neutrophil-based human tumor therapeutic regimens can be widely implemented in clinical practice, their safety and tolerability must be thoroughly analyzed. This means that high-quality clinical trials should be conducted to carefully evaluate the long-term efficacy and safety of neutrophil infiltration into tumors. The use of gene editing and synthetic biology technologies could significantly enhance their tumor-targeting ability, therapeutic efficacy, and biosafety. Despite the success of many therapeutic approaches in mouse tumor models, the exact functions and subpopulations of neutrophils, as well as the regulation of neutrophil polarization in different tumors, remain unclear. More efforts are still needed to optimize neutrophil-based therapeutic strategies and facilitate their clinical translation. Once the aforementioned challenges are addressed, neutrophil-based therapies could offer new strategies for cancer treatment.

The involvement of neutrophils in tumorigenesis, tumor development, and progression underscores the morphological plasticity and functional versatility of TANs. This review aims to discuss the mechanisms underlying the bidirectional anti-tumor and pro-tumor roles of neutrophils in tumor immunity, as well as the process of interconversion between these roles. It also considers the involvement and regulation of this process by various immune-related factors and other immune cells within the tumor microenvironment. Currently, the complex role of neutrophils in cancer encompasses not only their ability to promote or inhibit tumor progression but also a spectrum of polarization states. There remain many unresolved questions regarding the physiological and biochemical basis of neutrophil behavior in the tumor microenvironment. These include the specific metabolic processes during neutrophil-tumor interactions, the relationship between neutrophil polarization and maturation, the differences between activated and immature neutrophils, and the identification of nuclear morphology and the expression of specific surface markers in different subtypes of neutrophils or at various stages of neutrophil maturation. The identification of specific surface markers and the expression patterns of neutrophils across various stages of maturation is crucial. It is believed that targeting neutrophils in the tumor microenvironment will offer new insights for cancer therapy research. By addressing the role of neutrophils in the entire cycle of a tumor’s life activities and resolving the remaining issues in basic medical science, we can pave the way for novel therapeutic strategies.

Acknowledgements

Not applicable.

Author contributions

Haoxin Luyang wrote the manuscript and drew the figures. Feng Zeng, Yan Lei and Qian He collected the related papers and helped to revise the manuscript. Yanhong Zhou and Juan Xu designed and revised the manuscript. All authors reviewed the manuscript and approved the submitted version.

Funding

The present study was supported by the National Natural Sciences Foundation of China (82273219, 81672685) and the college student innovation and entrepreneurship project of Central South University (S202410533083).

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.

Contributor Information

Yanhong Zhou, Email: zhouyanhong@csu.edu.cn.

Juan Xu, Email: xujuan2611@hnca.org.cn.

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Data Availability Statement

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