Th17 cell function in cancers: immunosuppressive agents or anti-tumor allies?

Abstract

T helper (Th) 17 cells, a distinct subset of Th lymphocytes, are known for their prominent interleukin (IL)-17 production and other pro-inflammatory cytokines. These cells exhibit remarkable plasticity, allowing them to exhibit different phenotypes in the cancer microenvironment. This adaptability enables Th17 cells to promote tumor progression by immunosuppressive activities and angiogenesis, but also mediate anti-tumor immune responses through employing immune cells in tumor setting or even by directly converting toward Th1 phenotype and producing interferon-gamma (IFN-γ). This dual role of Th17 cells in cancer makes it a double-edged sword in encountering cancer. In this review, we aim to elucidate the complexities of Th17 cell function in cancer by summarizing recent studies and, ultimately, to design novel therapeutic strategies, especially targeting Th17 cells in the tumor milieu, which could pave the way for more effective cancer treatments.

Introduction

Numerous immune cell types are involved in the intricate process of identifying and killing cancer cells, which is mainly dependent on the immune system. Researching on the immunological components of the tumor microenvironment (TME) is crucial for both cancer immunotherapy and understanding the developmental paths of tumors [1, 2]. Since cancers originate from normal cells, it can be difficult for the immune system to identify and react to self-derived tumor cells [3]. Both innate and adaptive immune responses may be triggered by malignant cellular change [4]. Since discovery of T helper (Th) 17 cells in 2005 and after being thoroughly examined in the context of autoimmune disorders [5], Th17 cells are now understood to be a crucial cell type that promotes inflammation in a variety of pathophysiologic situations, including infections [6], autoimmunities [5], and cancer [7, 8]. These cells are a subset of CD4⁺ T cells which produce interleukin (IL)-17 (also known as IL-17 A), IL-17 F, IL-21, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-22 [9]. Engagement of naive CD4⁺ T cells into the Th17 subset relies on various cytokine cocktails including transforming growth factor beta (TGF-β), IL-6, IL-1β, or IL-21 [10]. IL-23 has been demonstrated to preserve Th17 cells’ pathogenic phenotype and survival, while not being necessary for their differentiation [11]. Upon steady state, Th17 cells are located in lamina propria of the small intestine but can be induced in any other tissues (more precisely in mucosal and epithelial barriers) to fight extracellular bacteria, viruses, and fungi [12]. Their primary physiological role of Th17 cells is to protect the host against extracellular pathogens at the mucosal surfaces [13]. The involvement of these factors extends to tissue inflammation and the development of several autoimmune conditions, including multiple sclerosis, rheumatoid arthritis, psoriasis, and inflammatory bowel disease (IBD) [14]. Although Th1 and Th2 subsets are considered definitive and mutually exclusive lineages, it seems that Th17 and regulatory T cells (Tregs) subsets do not represent stable differentiation processes and retain plasticity allowing them to adapt to different environments [12]. Th17 presence in the TME has unveiled a complex dichotomy; on the one hand, Th17 cells have been shown to facilitate tumor growth by inducing angiogenesis and promoting the survival of cancer cells [15]. On the other hand, they have a role in tumor elimination by releasing interferon-gamma (IFN-γ) and recruiting dendritic cells (DCs), CD8⁺ T cells, and natural killer (NK) cells to the tumor site [15]. This duality underscores the need for a deeper understanding of the factors that govern the behavior of Th17 cells in cancer. By summarizing the studies of previous scholars, we found that this high degree of plasticity is also imperative for the anti-tumor activity defined for Th17 cells in the development of autoimmunity because Th17 cells can even directly convert to the Th1 phenotype and produce IFN-γ to exert anti-tumor effects. To date, studies strongly indicate that Th17 cells influence the prognosis of cancer patients through their high plasticity and the secretion of inflammatory cytokines like IL-17. In this paper, we aim to explore the intriguing dichotomy of Th17 cells, examining the mechanisms behind their conflicting roles and discussing the potential implications of this cells in various cancers. By navigating through their immunosuppressive and anti-tumor activities, we seek to shed light on how these cells can be targeted or modulated for improved cancer treatment outcomes.

Different th cell subsets in cancer immunity

The process by which naive CD4 + T cells differentiate into distinct subpopulations of helper T cells is contingent upon the cytokines released by antigen presenting cells (APCs) and various precursor cells. These cytokines initiate a cascade of downstream signaling pathways that facilitate the initial activation, proliferation, and subsequent differentiation of naive T cells into specific effector cells [16]. Different T cell populations that have been characterized, are tightly involved in several cancers and inflammatory diseases [11]. In the tumor microenvironment (TME), a diverse array of cytokines seems to facilitate the differentiation of naive CD4 + T cells into various functionally specialized T helper (Th) subsets [17]. Each of these subsets subsequently influences the immune system’s capacity to combat tumors in distinct ways [12]. Interestingly, these Th subsets demonstrate a remarkable degree of plasticity, indicating their ability to modify their functional roles from one type to another in response to environmental signals [13] (Fig. 1).

Fig. 1

Different Th cell subsets in cancer immunity. In the tumor microenvironment (TME), a wide range of cytokines appears to promote the differentiation of naive CD4 + T cells into various specialized T helper (Th) subsets. Each of these subsets plays a unique role in modulating the immune system’s effectiveness against tumors. Furthermore, these Th subsets exhibit significant plasticity, reflecting their capacity to alter their functional characteristics in response to different environmental cues. Abbreviations: IL: interleukin, Th: T helper, Tfh: T follicular helper, TGF-β: transforming growth factor beta, TNF-α: tumor necrosis factor alpha, DCs: dendritic cells, Treg: regulatory T cell, CD40L: CD40 ligand

Th1

Research shows that Th1 cells are essential for promoting positive patient outcomes in different cancer types [18]. The cytokines IFN-γ and IL-12 are the main factors that stimulate the production of these powerful anti-tumor T cells [19]. IL-12 stimulates NK cells to produce IFN-γ, triggering the STAT1 and STAT4 signaling pathways in CD4⁺ T cells [19]. T-bet, also known as T-box expressed in T cells, is a crucial transcription factor that stimulates Th1 differentiation while inhibiting the growth of Th2 and Th17 cells as a result of this coordinated activation [9, 20]. Moreover, the secretion of IFN-γ by these developing Th1 cells generates a positive feedback loop that enhances Th1 differentiation even more [21]. Th1 cells employ multiple anti-tumor mechanisms, including the inhibition of angiogenesis and metastasis, as well as the induction of programmed cell death, or apoptosis, in cancer cells. Additionally, interferon-gamma (IFN-γ) promotes the activation of M1 macrophages, disrupts the function of regulatory T cells (Tregs), and triggers tumor dormancy and senescence [22]. These results are corroborated by clinical observations, which show that increased Th1 cell levels in the TME are associated with a favorable prognosis in a number of cancers, including laryngeal carcinoma, ovarian cancer, breast cancer (BC), melanoma, glioblastoma, colorectal cancer (CRC), and non-small cell lung cancer (NSCLC) [23,24,25,26,27,28]. It’s crucial to recognize that IFN-γ could have effects that vary depending on the situation. IFN-γ has been demonstrated to promote tumor spread and immune evasion in chronic inflammation [22]. To completely understand the intricate interactions between Th1 cells and the TME, more investigation is required.

Th2

Th2 cells are essential in mediating type 2 immune responses, orchestrating the removal of pathogens, allergens, and extracellular microorganisms [29]. In order to do this, they secrete a specific arsenal of cytokines, including IL-4, IL-5, IL-9, IL-13, and IL-25 [29]. These cytokines operate as important modulators of humoral immune responses which attract and stimulate immune effector cells, such as mast cells and eosinophils [30]. IL-4 seems to be a key factor in Th2 differentiation. This cytokine is released by a variety of cell types, including basophils, NKT cells, and existingTh2 cells and stimulates the STAT6 signaling pathway in naive CD4⁺ T cells [31]. The transcription factor GATA3, the main regulator of Th2 cell growth, is upregulated as a result of this activation [9, 21]. Historically, it has been believed that Th2 responses accelerate the growth of tumors by inhibiting Th1-mediated anti-tumor action and boosting angiogenesis. Nevertheless, new data points to a more complex function for Th2 cells, with certain elements perhaps aiding in the eliminating tumors [32]. The existence of Th2 cells and their secreted cytokines are linked to a poor prognosis in a number of malignancies, including melanoma, gastric, ovarian, pancreatic, and cervical cancers [33,34,35,36,37]. While the precise mechanisms by which Th2 cells promote tumor growth are still under investigation, several key pathways have been identified. Tumor immune escape appears to be significantly facilitated by Th2-associated cytokines [38]. Moreover, IL-10 can stimulate Tregs and inhibit DCs from presenting antigens, hence reducing the anti-tumor immune response [32]. Furthermore, IL-4 potentially enhances the metastatic potential of cancer cells by altering the phenotype of tumor-associated macrophages [39]. According to some publications, Th2 cells may have an anti-tumor effect in certain situations, such as chronic lymphocytic leukemia, BC, and Hodgkin lymphoma [40,41,42]. In these instances, a good prognosis for the patient was correlated with the presence of Th2 cells or their secreted cytokines. It has been demonstrated that IL-4 encourages eosinophil and macrophage infiltration into the TME [43]. Moreover, research conducted in vitro has shown that IL-4 might cause BC cells to undergo programmed cell death, or apoptosis [44].

Th9

Th9 was formerly thought to be a member of the Th2 lineage but now it is identified as a separate population. An increasing amount of research focuses on the possibilities of less-studied helper T cell populations in adaptive anti-tumor immunity, in addition to the well-known Th1 and Th2 subsets. The Th9 cell is one such subgroup; it was formerly thought to be a member of the Th2 lineage but now it is identified as a separate population [45]. Th9 cells are CD4⁺ T lymphocytes that produce IL-9 in addition to IL-10 and IL-21 [46]. Although like Th2 cells, Th9 rely on IL-4 signaling via STAT6 for their differentiation, but also TGF-β is a crucial cytokine [47]. Functionally, Th9 cells support type 2 immune responses and work with Th2 cells to eradicate extracellular parasites and trigger allergic reactions [48]. Th9 cells have different functions in hematological malignancies and solid tumors, and their effects on tumor formation are context-dependent. Numerous researches indicate that Th9 cells may have a pro-tumorigenic role in hematological malignancies [49]. Proposed mechanisms by which IL-9 may facilitate tumor promotion involve the augmentation of lymphoma cell viability through the reduction of oxidative stress levels [50] and the activation of Treg-mediated immunosuppression [51]. Clinically, aggressive lymphomas including Hodgkin’s lymphoma and large-cell anaplastic lymphoma have been linked to increased IL-9 expression [52]. Additionally, compared to healthy controls, patients with nasal NK/T-cell lymphoma had higher tumor cell IL-9 mRNA levels [53]. Studies indicate that Th9 cells primarily function as anti-tumor cells in solid tumors, in contrast to hematological malignancies [54]. Notably, extensive evidence in melanoma indicates that Th9 cells induce strong anti-tumor responses which involve the recruitment of DCs to the tumor site and the subsequent differentiation of tumor-specific CD8⁺ T cells [55,56,57,58]. In a similar vein, Th9 cells in BC facilitate anti-tumor immunity by secreting IL-9 and IL-21 [59]. But in some solid tumors, Th9 cells seem to play a more intricate function. For example, Th9 cells in hepatocellular carcinoma (HCC) have been shown to up-regulate CCL20, which has been involved in encouraging tumor growth [60]. Similarly, research on lung cancer indicates that Th9 cells may promote the migration and proliferation of cancer cells, hence aiding in the formation of tumors [61].

Th17

Th17 cells, a subset of CD4⁺ helper T cells, have been linked to a number of inflammatory conditions and have been implicated in autoimmune diseases [8]. A particular cytokine profile, comprising IL-17 A, IL-17 F, IL-21, and IL-22, is produced by these cells [9]. Naive CD4⁺ T cell development into Th17 cells is regulated by a specific cytokine milieu, which is mostly composed of TGF-β, IL-6, IL-1β, and IL-23 [8]. Furthermore, the Th17 cell transcriptional program is established by the master transcription factor RORγt, which is crucial [62].

A crucial element for the development of Th17 cells is HIF-1α; its deficiency leads to a reduction in the differentiation of these cells [63]. The commitment of naïve T cells into the Th17 lineage necessitates the selective control of genes associated with glycolysis, in which HIF-1 plays a crucial function in establishing the metabolic conditions necessary for Th17 development [64, 65]. This process seems to rely on mTORC1 downstream of the PI3K–Akt complex [63]. Additionally, it has been shown that mTORC1 exerts a positive control on the production of IL17 via many pathways, including STAT3, HIF-1α, and S6K2 [66].

A recent investigation has shown that humans’ diverse Th17 cell subgroups may be further classified into two primary groups according to the varying expression of chemokine receptors CCR4 and CXCR3: classical immunomodulatory Th17 and non-classical pro-inflammatory Th17. Classical Th17 is characterized by (CCR4⁺CXCR3⁻); they secrete large quantities of IL-17 and a low amount of IFN-γ. However, non-classical Th17 is identified by (CCR4⁻CXCR3⁺, also known as Th17.1 or Th1/Th17) secrete low amounts of IL-17 and high levels of IFN -γ, with a phenotype comparable to the Th1 [67].

The reported variations in Th17 cells’ functions within the TME are probably due to their phenotypic flexibility. Depending on the unique features of the tumor, Th17 cells may show pro- or anti-tumor traits. This complexity is further highlighted by the reciprocal and antagonistic regulation of Th17 and Treg differentiation pathways [68]. Numerous studies has investigated the relationship between the Th17/Treg ratio and patient outcomes in light of this interaction [69]. A disparity that benefits the Th17 or Treg populations may accelerate the growth of tumors by inducing excessive inflammation or suppressing the immune system’s ability to fight cancer, respectively [69]. Although a number of studies have found links between the Th17/Treg imbalance and various patient outcomes, such as survival and cancer grade [69,70,71,72,73], however, the nature of this imbalance appears to be significantly influenced by the specific type of tumor involved [74]. Th17 cells have the ability to both promote and prevent tumor growth. For example, they can stimulate angiogenesis and increase the survival of cancer cells, which can aid in the formation of tumor [75]. On the other hand, by producing IFN-γ and attracting immune effector cells to the tumor site, such as DCs, CD8⁺ T cells, and NK cells, they can also assist in the tumor elimination [15]. There is ample evidence that the relationship between Th17 cells and cancer is intricate and heavily context-dependent.

Th22

Th22 cells, recently discovered CD4⁺ Th subset, are distinguished by their production of IL-22, IL-13, and tumor necrosis factor alpha (TNF-α), but not IL-17, IFN-γ, or IL-4 [76]. Their differentiation from naive CD4⁺ T cells is driven by a specific cytokine milieu, including IL-6, IL-23, IL-1β, and TNF-α [76, 77]. A growing body of research indicates that Th22 cells may have a role in the development of tumors in a number of malignancies, including ovarian, gastric, lung, hepatocellular, and colon cancers [78,79,80,81,82]. The functional characteristics of IL-22, which have been demonstrated to suppress apoptosis, enhance tumor cell proliferation, angiogenesis, migration, the shift from epithelial to mesenchymal tissue, and metastasis, are most likely responsible for this connection [83,84,85]. It is important to notice that Th1 and Th17 cells can also contribute in production of IL-22 that present in the TME, meaning that Th22 cells are not the only ones that can produce IL-22 [86, 87].

T follicular helper (tfh) cells

Tfhs represent a distinct lineage of CD4⁺ Th cells, essential for the production of high-affinity antibody responses. They accomplish this by encouraging the growth of B cells and making immunoglobulin class switching easier [88]. IL-6 and IL-21 work together to drive Tfh cell differentiation by inducing the production of the transcription factor Bcl-6 and activating STAT3 signaling, which in turn polarizes the cells into Tfh effector cells [9, 88]. Tfh cells appear to have a context-dependent function in the genesis of cancer [89]. Circulating Tfh-like cells are associated with a poor prognosis in chronic lymphocytic leukemia, especially in later stages [89]. However, Tfh cell infiltration into the tumor is linked to a better prognosis and increased patient survival in non-lymphoid malignancies such as colorectal, lung, and BCs [90,91,92]. This implies that Tfh cells may have an anti-tumoral function in solid cancers. The creation of ectopic lymphoid tissues inside the TME is the suggested mechanism for this anti-tumor impact [93]. These organs function as centers for attracting more immune effector cells that are essential for the removal of tumors. Furthermore, Tfh cells may aid in the production of anti-tumor antibody responses by influencing B cell activity [93].

Tregs

About 10% of CD4⁺ T cells in healthy individuals are naturally occurring Tregs, or nTreg cells [94]. These cells are characterized by the constitutive expression of the FoxP3 transcription factor in the nucleus, along with CD25 and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) surface markers, all of which are critical for their suppressive function [95]. These cells are responsible in maintaining immunological self-tolerance [95]. However, they can also impede anti-tumor immunity and accelerate the course of cancer by controlling immune surveillance and suppressing effector T-cell responses [96], . In fact, poor survival outcomes and disease progression are correlated with higher nTreg levels in individuals with different malignancies [97]. Certain immunotherapies and targeted treatments may be less effective as a result of this immunosuppressive impact [98]. One mechanism by which nTreg cells suppress anti-tumor immunity involves CTLA-4-dependent downregulation of CD80 and CD86 expression on APCs [98]. This hinders the presentation of the tumor antigen and the consequent activation of tumor-specific T cells [98]. Interestingly, studies indicate that Treg cell-expressed programmed cell death protein 1 (PD-1) functions as a negative regulator of the suppressive activity of these cells [99]. Therefore, even though the goal of PD-1 blockade therapy is to revitalize fatigued CD8⁺ T cells, it’s possible that this treatment could unintentionally increase Treg cells’ suppressive function in the TME [99]. nTreg cells have the ability to secrete immunosuppressive cytokines such as TGF-β, IL-10, and IL-35, which can further impair anti-tumor immunity [100].

Th17 plasticity and cytokine profile in cancer

Unlike Th1 and Th2, Th17 cells are not a “fixed” subset. They can convert into other T helper types by the effect of the microenvironment, a phenomenon known as “Plasticity” [101]. Research indicates that Th1 and Th2 cells are regarded as more phenotypically stable, whereas Th17 cells demonstrate a significant level of plasticity, enabling them to differentiate into various subtypes in response to particular stimuli or pathogenic environments [102, 103].

Given the great phenotypic flexibility of Th17 cells, it is not unexpected that the available data about Th17 cells’ role in cancer is wildly contradictory and tumor-specific [68]. Th17 cells are more plastic compared to other T cells because of their capacity to adopt a variety of functional phenotypes and their intricate nature, which involves both cytokine-dependent and -independent actions [104]. A unique feature of RORγ as compared to T-bet or GATA3, is that its expression is not stabilized by positive feedback loops, making it extremely susceptible to variations in the environment [105]. These variations result in strong phenotypic plasticity at the cellular level. Notably, phenotypic shifts between Th17 cells and every other Th subtype have been documented [106]. One of the most significant subtypes of Th17 plasticity is Th17/Th1. These cells show double-positive Th1/Th17 features, co-expressing cytokine receptors (IL-12Rβ2 and IL-23R) and distinctive transcription factors (RORγt and T-bet) [67]. Studies conducted in vitro demonstrate the importance of growth factors and cytokines in plasticity [107, 108]. While adequate TGF-β promotes the maintenance of the Th17 phenotype, low or missing TGF-β with adequate IL-12 and IL-23 cytokines appears to favor conversion towards Th1 by activating STAT4 [107, 108]. The fact that Th17 plasticity is unidirectional is an important conclusion from earlier studies. It is easy for Th17 cells to become Th1-like cells, but not the other way around [102]. These Th17-derived Th1-like cells have a unique surface marker profile (CD161, CCR6, and IL-17RE) that allows them to be identified from traditional Th1 cells [62, 109]. Furthermore, they have a distinct cytokine profile, co-expressing pro-inflammatory mediators such as IL-26, chemokine (C-C motif) ligand 20 (CCL20), IFN-γ, GM-CSF, and IL-22 [12, 109]. Expression of these cytokines depends on the secretion of IL‐6, TGF‐β, IL‐1β, IL‐12 and IL‐23 by APCs during differentiation or during reactivation of already‐differentiated classical Th17 cells [67]. Notably, it has been revealed that Th17/Th1 differentiation can be stimulated by DCs expressing the notch ligand DLL4 through direct activation of T-bet and RORγt [110]. The discovery of Th17 cell infiltration via chemokine receptor interactions into a variety of tumor forms, such as B cell (non-hodgkin) cancer, BC, colon cancer, gastric cancer, hepatocellular cancer, melanoma, myeloma, ovarian cancer, pancreatic cancer, and so on, in recent research has revealed even another level of intricacy [7, 12, 111,112,113]. Furthermore, recent studies indicate that RORγt⁺ and T-bet⁺ cells within tumor-infiltrating lymphocytes (TILs) may be in balance in a variety of malignancies, including ovarian and BC [114]. The differentiation pathways of Th17 and Treg CD4⁺ T cell subsets are quite similar. TGF-β alone drives Treg cell differentiation while it induces Th17 cell differentiation and inhibits Treg cell differentiation in the presence of other cytokines such as IL-6 or IL-21 [10]. As the constitutive ratio of Tregs and Th17 cells is modified in the TME, human Th17 cells exhibit substantial developmental plasticity and differentiate into Treg cells, an immunosuppressive subset infiltrating the TME [115]. Even in the presence of Th17-polarizing cytokines, Th17-derived Tregs avoid reverting back to the Th17 phenotype, suggesting that this conversion is highly persistent [116]. Ye et al.‘s in vitro research provides strong support for this trans differentiation: first, they obtained a Th17 subpopulation by stimulating TILs from ovarian and colon cancers with a CD3 monoclonal antibody as well as IL-2; and then, they used flow cytometry to detect the results after amplifying this subpopulation three times and found a significant increase in the FoxP3⁺ cell subtype with an obvious decrease in the IL-17⁺ cells, a TCR stimulation dependent differentiation [116]. It has been shown that Th17⁺FoxP3⁺ double-positive T cells exist in a variety of tumor environments. These cells are highly prevalent in the colitis microenvironment linked to colon cancer, according to Kryczek et al. In terms of function, these cells encouraged the production of inflammatory cytokines in the colitis tissues while inhibiting T-cell activation [117]. Similar findings were reported in cases of esophageal cancer in humans [118]. Research on B-cell non-Hodgkin’s lymphoma indicates that cancerous B cells have the ability to upregulate FoxP3 expression and encourage the growth of Treg cells, which in turn inhibits Th17 differentiation and induce a suppressive TME [111]. Beyond Th17/Th1 and Th17/Treg plasticity, studies indicate that people with asthma have Th17/Th2 hybrid cells in their blood. These cells generate a mixed cytokine profile consisting of IL-17, IL-22 (Th17), IL-4, IL-5, and IL-13 (Th2), and they co-express the transcription factors GATA3 and RORγt, which are indicative of both lineages [119]. It has also been demonstrated that Th17 cells in peyer’s patches take on the Tfh phenotype [120]. Researchers have shown that Th17 cells within Peyer’s patches may dynamically change to Tfh cells (expressing Bcl6, CXCR5, PD-1, and IL-21) by the use of IL-17 fate reporter mice. This process promotes the formation of IgA-secreting germinal center B cells [120]. Figure 2 provides a schematic representation of the plasticity of Th17 cells as they differentiate into other T cell phenotypes.

Fig. 2

Th17 plasticity and cytokine profile in cancer. Th17 cells differentiate into various subtypes under the influence of different cytokines, exhibiting both anti-tumor and pro-tumor activities within the tumor microenvironment. Each subtype secretes distinct cytokines and chemokines that play a significant role in shaping the tumor response. Abbreviations: IL: interleukin, Th: T helper, TGF-β: transforming growth factor beta, IFN-γ: interferon-gamma, Treg: regulatory T cell, GM-CSF: granulocyte-macrophage colony-stimulating factor, CCL-20: C-C motif ligand 20, Tfh: T follicular helper, IL-17RE: IL-17 receptor E, CCR: CC chemokine receptor

Th17 dual function in various human cancers

The impact of Th17 cells on cancer development is multifaceted, as they can either facilitate tumor progression or impede tumor growth, contingent on the individual characteristics of the tumor (Fig. 3). This section presents findings on the opposing roles of Th17 cells in BC, melanoma, lung cancer, CRC, and HCC.

Fig. 3

Th17 dual function in various human cancers. The TH17 cell subset can promote tumor progression through the secretion of cytokines such as IL-17 A and IL-22, which facilitate tumor cell proliferation, angiogenesis, metastasis, differentiation into Treg cells, and the recruitment of myeloid-derived suppressor cells (MDSCs), thereby exerting pro-tumor effects. Conversely, this cell lineage can also inhibit metastasis, angiogenesis, and tumor-associated macrophages (TAMs) through the release of cytokines including IL-1, IL-6, IL-17 A, and IL-17 F. Additionally, it can stimulate the recruitment and activity of cytotoxic T lymphocytes (CTLs), TH1 cells, dendritic cells (DCs), natural killer (NK) cells, and neutrophils, resulting in anti-tumor effects. Abbreviations: IL: interleukin, DCs: dendritic cells, IL-17R: IL-17 receptor, PD-L1: programmed cell death ligand 1, TAMs: tumor associated macrophages, Th: T helper, NK cell: natural killer cell, MMP: matrix metalloproteinase, CXCL: C-X-C motif ligand, VEGF: vascular endothelial growth factor, Treg: regulatory T cell, MDSC: myeloid-derived suppressor cell, TGF-β: transforming growth factor beta, CTL: cytotoxic T lymphocyte, CTLA-4: cytotoxic T-lymphocyte associated protein 4, RA: retinoic acid

BC

BC is a global problem due to its high mortality and prevalence, especially among women. Despite treatment progress, no definitive cure for BC has been reported [1]. However, substantial research has been done to find effective treatments and identify BC progression mechanisms and causes [121, 122]. BC spreads due to many reasons, including Th17 cells’ chemokines, cytokines, and inflammatory pathways [12]. Karpisheh et al. gathered comprehensive evidence of the dual role of Th17 in BC pathogenesis [123]. The dual roles of Th17 cells in BC, encompassing both tumor-promoting and anti-tumor functions, are examined in this section. Regarding the tumor-promoting characteristics of Th17 cells, a multitude of studies have indicated an increased presence of these cells in the tumor tissues and PBMCs of BC patients. Notably, Th17 cells exhibit heightened activity in individuals with advanced stages of the disease [124, 125]. Du et al. found that breast tumor tissue expressed IL-17. By increasing tumor microvessel accumulation, IL-17 boosted angiogenesis, metastasis, tumor cell proliferation and growth, and BC progression rate. In addition, they found that IL-17 injection into tumor-bearing animals greatly enhanced tumor progression, but in vitro exposure did not [126]. The findings of Chen and colleagues established a correlation between elevated levels of IL-17 secretory cells and a higher histological grade in BC [127]. In another study, IL-22, a major Th17 cytokine, increased angiogenesis, proliferation, and tumorogenesis [128]. According to a different study on BC patients, IL-17 significantly increased the expression of the vascular endothelial growth factors (VEGF), CXCL8, matrix metalloproteinase (MMP)-2, and MMP-9, promoting the growth of tumor cells. Tumor invasion and increased expression of IL-17 A were positively correlated with the quantity of Treg cells in invasive breast tumors [129]. Thibaudin et al. found that ectonucleotidase-expressing CD25^high Th17 cells grew rapidly in tumor tissue and suppressed CD8⁺ and CD4⁺ T cells by inhibiting and activating them, respectively. They suggested that these cells hindered the immune system’s anticancer responses [130]. Moreover, it was found that Th17 cells regulate CXCL1 expression throughout cancer growth. Evidence suggests that CXCL1 expression on tumor cells and its interaction with the CXCR2 receptor can activate the NF-κB/ AKT pathway, leading to metastasis, angiogenesis, growth, and progression of BC [131]. Evidence shows that aggressive molecular subtypes TN, Luminal B, and HER2 have higher levels of IL-17 A than less aggressive Luminal A. Also, it was demonstrated that Th17 increased BC risk [132]. Scientists also indicated that IL-17-producing neutrophils and γδ cells boosted BC cell invasion and metastasis. Breast tumor cells stimulated neutrophil polarization and proliferation, suppressing CD8⁺ T cells and increasing dissemination to adjacent organs [133]. IL-17 A also promoted cell growth and proliferation, according to Kim et al. [134]. Moreover, in vitro, recombinant IL-17 had minimal influence on cancer cell proliferation in mouse BC cells, while angiogenesis and tumor size increased in animals [126]. A study by Huang et al. found that Treg cells increased IL-17RB production in BC cells by secreting TGF-β1 and activating the Smad2/4/3 signaling pathway in tumor-draining LNs (TDLNs), leading to cancer cell proliferation, angiogenesis, and metastasis [135]. Additionally, IL-17E has been shown to generate anti-tumor responses in vitro and in vivo. IL-17E’s anti-tumor effect was linked to increased peripheral blood eosinophils and IL-5 levels in tumor-bearing animals [136]. In contrast, Jiang et al. found that macrophages and CD4⁺ T cells released IL-17E in a breast tumor model. IL-17E suppression reduced tumor cell growth, proliferation, and metastasis by decreasing macrophages and type 2 T cells in the TME. They found that inhibiting this cytokine may help cure metastatic BC [137]. Further research is required to explore the influence of IL-17E on the treatment and progression of BC, given the inconsistencies observed in these two studies [123].

On the other hand, Th17 cell exhibits an anti-tumor characteristic. In this regard, research indicates that Th17 cell number is positively linked to IL-6, IL-17, and IL-1β cytokine expression and negatively linked to increased metastatic lymph nodes and tumor cell angiogenesis. In BC tissues, more Th17 cells increased anti-tumor immune responses [138]. Therefore, Faucheux et al. also showed that boosting Th17 cell populations improved patient survival. In BC tissues, Th17 cell expansion induced anti-tumor immune responses, limiting BC development [139]. Numerous elements lead to the existence of contradictions in the literature. One notable paradox is the limited number of studies indicating that Th17 cells confer protection to patients with BC. The scarcity of research utilizing animal models complicates the extrapolation of these findings to human subjects. Consequently, additional research is warranted. Various studies have identified phenotypic variations of BC within individual patients, which may account for these inconsistencies. The immune responses, underlying causes of the disease, and responses to treatment differ among the various BC phenotypes. Therefore, it is essential for future research to evaluate the frequency and functionality of Th17 cells across different BC phenotypes [123].

Melanoma

Melanoma is a tumor derived from melanocytes, specialized pigmented cells, mainly found in the skin [140, 141]. The 17 cells are common in the microenvironment of melanoma. However, the role of these cells in tumor immunopathology is paradoxical as Th17 cells have shown both antitumor and pro-tumor effects in melanoma [75]. Chen and Gao have gathered sufficient evidence of this dual role of Th17 cells in melanoma [142]. Based on recent studies, there are at least two distinct immunological phenotypes in melanoma. One type is the Th17 immune phenotype (class A), characterized by high expression of WNT5A, increased cyclin activity, and cancer-testis antigens with a poor prognosis. A more differentiated state, increased reactivity to immune cytokines, and an improved prognosis is linked to the Th1 immunological phenotype of class (B) [143]. Metastases exhibiting a Th17 phenotype were more frequently BRAF mutated when comparing class comparisons between BRAF mutant and wild-type metastatic melanoma models. Furthermore, genes connected to the IL-17 pathway showed differential expression in BRAF mutants compared to wild-type models. Therefore, in the case of malignant melanoma, Th17 cells may also exert a significant pro-tumor effect [144, 145]. Multiple lines of evidence show that Th17 cells in melanoma can have strong pro-tumor effects. Reduced apoptosis, enhanced invasiveness, and increased metastatic behavior have all been linked to BRAF mutations [146]. Studies have shown that Th17-derived IL-17 is related to melanoma tumor angiogenesis, promoting the growth and survival of tumors [147, 148]. According to Lin Wang et al. IL-17 promoted the secretion of IL-6 by directly affecting cells that express IL-17 receptors, including fibroblasts, endothelial cells, melanoma cells, and DCs. As a consequence, the melanoma growth was accelerated. Following the activation of oncogenic STAT3 by IL-6 in melanoma cells, the expression of pro-survival genes such as Bcl-2 and Bcl-xl was increased [149]. Additionally, the Th17/Tregs plasticity in the melanoma microenvironment may be another mechanism involved in the Th17 cell’s pro-tumor impact in melanoma. Th17 cells can inhibit anti-tumor immunity and serve as regulatory cells. Tregs are produced through lineage conversion of Th17 cells [150, 151]. The intermediate phenotypes that co-express the transcript components FoxP3 and RORγt are the outcome of this conversion [151, 152]. Following anti-CD3 antibody stimulation, tumor-infiltrating Th17Th1cells can express FoxP3, CD25, and CTLA4, which are markers of Treg cells, and produce levels of IL-10 and TGF-β1 [153].

However, some other studies demonstrated evidence of anti-tumor effects of Th17 cells. For example, the adoptive transfer of Th17-polarized cells specific to tumors into large, well-established B16 melanoma mice was more successful than Th1 cells at mediating the eradication of advanced melanoma. IFN-γ and IL-17 production were required for this therapeutic effect to occur [154]. Adoptive transfer of Th17 cells specific to tumors also inhibits the growth of tumors, according to another study [155]. The impact of Th17 cells in eradicating melanoma was hindered by deficient IFN-γ or IL-17 A [147]. Martin-Orozco et al. discovered that Th17 cell treatment induced a striking activation of tumor-specific CD8⁺T cells, which were essential for the anti-cancer effect [155]. Tumor-infiltrating Th17 cells induced the expression of CCL2/20 in tumor tissues, which attracted DCs, CD4⁺ and CD8⁺ T cells, and other inflammatory leukocytes to promote anti-tumor immunity [155, 156]. Additionally, Th17 cells can boost CD8⁺ T cells to have an anti-tumor effect. In another study, researchers primed TRP-1 transgenic Th17 cells and Pmel-1 T cell receptor (TCR) transgenic CD8⁺ T cells ex vivo using a RORγ agonist. They discovered that these cells could successfully regress melanoma when compared to those Th17 cells that were not treated. The anti-cancer impact was significantly increased in mice with existing melanoma when co-infused with equal quantities of TRP-1, Th17 cells, and Pmel-1 Tc17 cells. These findings support earlier results and provide additional evidence that Th17 cells can enhance CD8⁺ T cells to have anti-tumor effects [157]. Based on the observation that Th17 cells that were IL2^−/− and Kb^−/− (without major histocompatibility complex type I; MHC I) lost their anti-tumor immunity, it is possible that Th17 cells stimulated the CTL response via IL-2 and peptide/MHC-I, which can be recognized by CD8⁺ T cells and induce CD8⁺ T cell activation. The results indicate that Th17 cells present in the tumor may have a dual role, acting as both effectors and regulators in the melanoma microenvironment. Therefore, Th17 cells may play a role in the development of melanoma. This process may be influenced by myeloid-derived suppressor cells that infiltrate the tumor and promote the conversion of Th17 cells to Tregs through the secretion of TGF-β and retinoic acid [158].

Lung cancer

NSCLC comprises the majority of lung cancers [159] and is the primary cause of death in cancer patients worldwide [160]. This unfortunate outcome is probably related to the lack of a comprehensive understanding of the NSCLC TME, which is a complex mixture of immune cells, fibroblasts, lymphatic and blood vessels [161]. This microenvironment aids tumor cells in proliferation, invasion, and metastasis and contributes to disease progression [162]. Several studies aimed to identify the role of IL-17 and Th17 specifically in NSCLC progression [163, 164]. Many of these studies found an increased frequency of Th17 as well as enhanced production of IL-17 in patients [163, 165, 166]. IL-17 A was shown to be able to promote the stemness, migration, and invasion of NSCLCs through STAT3/ nuclear factor kappa B (NF-kB)/Notch1 signaling pathways. Furthermore, blocking these pathways indicates capability to suppress NSCLC stemness, migration, and invasion. In addition, Th17 cells in NSCLC were strongly correlated with poor prognosis [163] and poor survival of NSCLC patients [167]. The recruitment of these cells appears to be a consequence of Kras mutation in lung epithelial cells as explained by Chang et al. [168]. IL-17 produced by Th17 contributes to inflammation, tumor growth, and recruitment of tumorigenic cells [168]. Armstrong et al. compared the Th17/IL17A axis in the TMEs of K-ras-driven and Ptsd/d NSCLC models and elaborated on mechanisms underlying the dual role of Th17 in NSCLC [169]. They discovered that in K-ras-driven mice, Th17 cells were drawn to the TME, promoting tumor cell proliferation. Th17-derived IL17A attracted myeloid derived suppressor cells (MDSCs) to suppress the anti-tumor function of CD8⁺ T cells. IL17A can directly cause tumor cells to produce more IL-6. IL-6 can work in two ways: autocrine to promote tumor cell proliferation and paracrine to enhance MDSC recruitment. MDSC invasion can also be boosted through GM-CSF, granulocyte-colony stimulating factor (G-CSF) produced by tumor cells. On the contrary, Th17/IL17A in the TME of the Ptsd/d NSCLC model inhibits tumor growth. Th17 cells are essential for the recruitment of CD103⁺ DCs, which activate CD8⁺ T cells for anti-tumor action. IL17A increases the expression of IL-17R and CD86 on CD103⁺ DCs, which provides signals for CD8⁺ T cell activation. Activated CD8⁺ T cells release IFN-γ, which activates both CD8⁺ T cells and DC tumoricidal activity, resulting in tumor cell death. IL17A may suppress CD206⁺ tumor-associated macrophages (TAMs), reducing PD-1 and programmed death ligand 1 (PD-L1) interactions between lymphocytes and TAMs and allowing lymphocytes to exert anti-tumor activity.

Furthermore, Th17 cells enhanced the production of chemoattractants CCL2 and CCL20 in the microenvironments of lung tumors and facilitated the recruitment of different inflammatory leukocytes (DCs, CD4+, and CD8 + T cells). Experimental evidence has demonstrated that Plasmacytoid dendritic cells (pDC) stimulated by CpG-activated and antigen presentation trigger the differentiation and growth of Th17 cells, resulting in the production of significant quantities of additional inflammatory cytokines, including IFN-γ [170]. When pDCs lack MHC II expression, the proliferation of Th17 cells in tumor tissue is diminished, and the Th17 response is impaired, resulting in a decline in the recruitment of immune cells such as cytotoxic T lymphocytes (CTL), which eventually contributes to tumor development [171].

The overall body of research indicates that Th17 cells have opposing roles in distinct genetic drivers of cancer, while some critical gaps in our understanding still need to be filled. It seems that identical immunological contexts elicit varied responses from various malignancies [169].

CRC

CRC is the most common cancer in the digestive system and is the second leading cause of cancer-related death; with a mortality rate of 8-9%, often diagnosed in advanced stages and with low overall survival rates. Chronic inflammation is linked to tumorigenesis, with local inflammation in tumor tissue being infiltrated by inflammatory immune cells, which can either progress or suppress tumor cell survival and growth [172,173,174]. Human CRCs are characterized by the presence of CD4⁺ T lymphocytes and macrophages producing IL-17 A, which contribute to poor prognosis. These cells, which are abundant in CRCs and have potent immunosuppressive functions, sustain oncogenesis and tumor progression. Studies have shown that IL-17 A, IL-17 F, IL-21, and IL-22 are overexpressed in CRCs, leading to reduced disease-free survival (DFS) in patients with these conditions [79, 175,176,177,178]. Doulabi et al. found that circulating Th17 and Th22 cells in CRC patients were significantly higher than in healthy controls. Infiltrating Th1, Th17, Th22, and CD4⁺ cells co-producing IL-17/IL-22 were also higher in tumor tissues compared to para-tumor tissues. The percentage of circulating and intra-tumoral Th17, Th22, and CD4⁺ cells co-producing IL-17/IL-22 was higher in advanced stages [172]. Another study examined IL-17 A dynamics along the human colorectal adenoma-carcinoma spectrum and has found that the expression of IL-17 A, at both the mRNA and protein levels, was significantly increased in the adenoma stage and persisted to the CRC stage [179]. It has been found that a high RORγt/CD3 ratio correlated with lymph node metastasis and is a decisive prognostic factor for shortened postoperative survival, suggesting Th17 cells may increase the metastatic ability of tumor cells in CRC [180]. A recent investigation revealed that TWEAK, a cytokine synthesized and released by Th17 cells, interacts with Fn14 receptors present on malignant cells. This interaction facilitates the migration and invasion of colorectal cancer (CRC) cells to the liver, thereby contributing to the development of colorectal cancer liver metastasis (CRLM) [181]. Single-cell RNA sequencing analysis revealed distinct distributions of nonmalignant cells within the primary tumors of patients diagnosed with metastatic colorectal cancer (mCRC) in contrast to those with non-metastatic colorectal cancer. Notably, this analysis indicated that Th17 cells were predominantly localized in the primary lesions associated with mCRC [181].

Th17 also has anti-tumor effects. Previous studies have demonstrated that the anti-tumor effect of IL-17 in various cancer types is related to enhanced recruitment and activity of lymphocytes, NK cells, and DCs into the tumor site and production of the anti-tumor cytokine IFN-γ [182,183,184]. IL-17 F is another potential factor involved in the development of CRC. Tong et al. have shown a protective effect of IL-17 F in the development of CRC. They found decreased tumor growth of IL-17 F-transfected HCT116 cells compared to that of mock transfectants when transplanted into nude mice. They also showed decreased VEFG and angiogenesis in IL-17 F overexpressing tumor cells [185].

In favor of the dual role of Th17 tumor-infiltrating cells, ex vivo analysis showed that tumor-infiltrating IL-17⁺ cells mainly consist of CD4⁺ Th17 cells with multifaceted properties. As a result of IL-17 secretion, CRC-derived Th17 triggered the release of pro-tumorigenic factors by tumor and tumor-associated stroma. However, on the other hand, they favored the recruitment of beneficial neutrophils through IL-8 secretion, and they drove highly cytotoxic CCR5 + CCR6 + CD8 + T cells into tumor tissue through CCL5 and CCL20 release. According to these findings, the presence of intra-epithelial, but not of stromal Th17 cells, positively correlated with improved survival [186].

HCC

HCC is one of the most common cancers worldwide. It has low overall survival (OS) rates due to factors such as distant metastasis, local recurrence, treatment resistance, and lack of early diagnosis, despite advancements in molecular biology and cancer therapy [187]. Th17 cells play complex roles in inflammation and tumor immunity. They express the transcription factor, RORγ, and secret cytokines, including IL-17 A, IL-17 F, and IL-22, IL-21, which act as a pro-inflammatory mediator. IL-17 is generally believed to induce chronic inflammation and has pro-tumorigenic effects, and accumulating evidence indicated that Th17 cells promoted HCC development and were associated with poor survival [188]. Zhang et al. studied the distribution of Th17 cells in 178 HCC patients. There were increased Th17 cells in tumor tissues when compared to non-tumor regions, and intra-tumoral IL-17 producing cell density was an independent prognostic factor for significantly shorter overall OS and DFS [188, 189]. A study found an imbalance in Treg/Th17 cells in HCC patients’ PBMCs. The increased numbers of Treg and Th17 cells were positively correlated with HCC tumor stage and size, suggesting Treg and Th17 cells may promote HCC invasion and progression, and a Treg/Th17 cell imbalance could be a key indicator for HCC progression and prognosis. Th17 cells promote tumor growth through IL-6-induced angiogenesis and inhibit it by amplifying cytotoxic lymphocyte presence [187]. Tumor-derived chemokines like monocyte chemoattractant protein-1 (MCP-1) and RANTES influence Th17 cell recruitment to tumor contexts. Th17 cells are found in tumor-infiltrating T lymphocytes in cancer patients, indicating their potential recruitment, induction, or development in the TME. This infiltration is related to poor prognosis in HCC, CRC, and pancreatic carcinoma [124, 189]. Accumulation of intra-tumoral IL-17-producing cells may promote tumor progression by fostering angiogenesis. Additionally, these IL-17-producing cells found within the tumor could potentially be used as a prognostic marker [124, 189]. The presence of IL-17 A-positive cells in tumor tissues has been associated with increased metastasis and a poorer prognosis in hepatocellular carcinoma (HCC). Subsequent studies have revealed that this correlation arises from IL-17 A’s capacity to promote cell migration by activating NF-kB transcription factors and increasing the expression of MMP-2 and MMP-9 [190, 191].

Huang et al. conducted a study on thermal ablation for treating HCC in mice. The study found that thermal ablation decreased Th17 cell frequency in peripheral blood, increased Treg cell frequency, and significantly downregulated IL-17 and IL-23 levels while upregulating IL-10 and TGF-β levels, suggesting that Th17 plays a crucial role in cancer promotion [192]. Another study found that Th17 cells express higher miR-132 compared to primary CD4⁺ cells. It positively regulates Th17 cell differentiation, enhances IL-22 production, and improves the function of Th17 on hepatic stellate cells (HSCs) for their tumor-promoting effects [193]. In hepatitis B virus (HBV)-related HCC, intra-tumoral densities of Th17 cells were augmented. These Th17 cells were thought to promote tumor progression and correlate with poor survival rates by fostering angiogenesis. In patients with HCC, high expression of intra-tumoral IL-17 and IL-17 receptor E were reported, associated with poorer survival rate and increased recurrence [194].

Anti-programmed cell death ligand 1 (PD-L1) therapy is recognized as a potential strategy for addressing hepatocellular carcinoma (HCC). Nevertheless, resistance to this treatment frequently develops in nearly all cases. Studies have indicated an elevated infiltration of pathogenic Th17 cells in HCC tissues that exhibit drug resistance. These Th17 cells produce IL-17 A, which promotes the upregulation of PD-L1 on HCC cell surfaces, thereby contributing to the resistance against anti-PD-L1 therapy and exacerbating the clinical scenario [195].

Th17 cells can also prevent tumor cell apoptosis, decrease anti-tumor responses, increase tumor angiogenesis, and stimulate tumor metastasis and invasion. Experimental evidence suggests that IL-17 can also suppress tumors during tumorigenesis and metastasis [64]. In various human cancers, CD3⁺ CD4⁺ RORγ⁺ cells are present at higher frequencies in the TILs than in PBMCs, suggesting their role in anti-tumor immunity. IL-17 A is a direct target of RORγ, which is the key transcription factor controlling the development and function of CD4⁺ Th17 and CD8⁺ Tc17 cells. Xiao Hu et al. identified synthetic agonists that selectively activate RORγ. They enhance the effector function of type 17 cells by increasing the production of cytokines/chemokines such as IL-17 A and GM-CSF, augmenting the expression of co-stimulatory receptors like CD137, CD226, and improving survival and cytotoxic activity. They also attenuate immunosuppressive mechanisms by curtailing Treg formation, diminishing CD39 and CD73 expression, and decreasing levels of co-inhibitory receptors, including PD-1 and T cell immunoreceptor with Ig and ITIM domains (TIGIT) on tumor-reactive lymphocytes [114].

Hepatocellular carcinoma (HCC) is classified as a hypermetabolic neoplasm. The unrestrained growth of the tumor, coupled with an insufficient oxygen supply within the TME, has been shown to lead to the upregulation of HIF-1α. This factor is posited to play a crucial role in activating RORγt, functioning through the formation of a tertiary complex with RORγt and the recruitment of p300 to the promoter region of IL-17. Additionally, HIF-1α is known to inhibit the development of Tregs by interacting with FoxP3 and promoting its degradation via the proteasomal pathway [196,197,198,199,200,201,202].

Potential clinical implications of manipulating Th17 cells in the context of cancer therapies

Considering the conflicting findings about the Th-17 cell’s pro- and anti-tumor properties, it may be necessary to tailor treatment plans to each patient’s specific cancer, stage, and even associated mutations in order to determine whether Th17 activation or inhibition would be more beneficial. A clear therapeutic goal for patients with malignancies that Th17 cells worsen is to decrease the quantity of these cells in the tumor microenvironment. The mice lung cancer model demonstrated tumor reduction upon IL-17 suppression, according to a study by Chang et al. This reduction was due to a decrease in tumor cell proliferation and angiogenesis [184]. In contrast, clinical trials aimed at enhancing particularly targeted T cell populations have showed significant potential in the treatment of cancer [36]. Notably, Paulos and colleagues found that the activity of human Th17 cells was increased when they were stimulated with CD3 and ICOS agonists, as compared to when they were activated with CD28, when transferred into mice with tumors [177]. The substantial antitumor response observed after infusing Th17 cells into mice with specific types of cancer, such as melanoma, suggests that further research aimed at directing and utilizing these cells to eliminate tumor tissue in clinical settings could offer therapeutic possibilities for a wide range of malignancies [67]. In addition, for individuals with increased Th17-based inflammation in the tumor microenvironment, addressing Th17 cells or cytokines specifically may have promise [67]. Using the fully-humanized anti-IL-17 A monoclonal antibody secukinumab (AIN457) to treat ER- or triple-negative breast cancer in mice increased antitumor immunity (CD4 + and CD8 + T cells), decreased PDL-1 expression, and reduced Treg cell infiltration [172]. Interestingly, a combination treatment approach [203] anti-IL-17 A (secukinumab) and anti-PDL1 (pembrolizumab) improved antitumor immunity in support of its eradication [100]. Contrarily, researchers found that exposing breast cancer cell lines to IL-17E had an anti-tumorigenesis impact [204]. Discrepancies in results may be attributed to variations in experimental circumstances and environments [7]. Important factors to consider include the timing of breast cancer cells exposure to IL-17, the type of cells present, and the stage of the disease [50]. Furthermore, substances like phosphodiesterase-4 inhibitor (PDE-4 inhibitors) and JAK/STAT inhibitors have the ability to influence the IL-17/Th17 signaling pathway and might potentially be utilized in the treatment of lung cancer in a similar manner. Targeting this pathway could hold great promise as a treatment for lung cancer, according to the safety and effectiveness of the drugs now under development. There is new evidence that the IL-17/Th17 and PD-1 pathways are connected, which opens the prospect of a synergistic effect between anti-PD(L)1/anti-IL-17 and anti-PD(L)1/anti-IL23 targeting [205]. The available data indicates that the targeting and reprogramming of several downstream signaling pathways of IL-17 A could be a crucial complementary strategy to enhance the effectiveness of conventional cancer therapy [89]. Thus, additional investigation is required in the future to develop anti-cancer tactics that specifically focus on IL-17 signatures and their associated signaling pathways.

Table 1 Different Th subsets and their function in the TME

Conclusions

Th17 cells are acknowledged as a crucial cell type that promotes inflammation in different pathophysiologic conditions. These cells infiltrate several forms of cancers. Th17 cells can display either pro-tumor or anti-tumor properties, depending on the unique characteristics of the tumor. In this review, we have gathered evidence of the contradictory role of Th17 cells in BC, melanoma, lung cancer, CRC and HCC. Pro-tumor effects of Th17 cells range from promoting metastasis, tumor growth and angiogenesis to recruiting MDSDs and increasing Treg to suppress anti-tumor responses. On the other hand, Th17 cells’ anti-tumor effects might include recruitment of DCs and NK cells, activating CD8⁺ T cells and subsequent tumor cell death, suppressing CD206⁺ TAMs and reducing PD-1/PD-L1 interactions and production of anti-tumor cytokines. This opposing behavior of Th17 cells might be related to different immune responses, genetic or phenotypic variances within each cancer or small number of studies on this matter. Given the crucial significance of the T17 population in the advancement of various illnesses, it is important to understand the mechanisms underlying T17 cells’ functions in different types of malignancies. This area of research holds great potential for cancer therapy development.