Ferroptosis in TNBC: interplay with tumor-infiltrating immune cells and therapeutic implications

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options and a poor prognosis. Immunotherapy has emerged as a promising approach for TNBC, with tumor-infiltrating immune cells (TICs) in the tumor microenvironment (TME) serving as a critical cellular basis for its efficacy. However, the success of immunotherapy in TNBC is often limited due to the immunosuppressive nature of the TME and the heterogeneity of TNBC. Ferroptosis, a form of iron-dependent programmed cell death regulated by metabolic networks including iron, glutathione (GSH), and lipid metabolism, has shown potential to enhance anti-tumor immunity. Recent studies have demonstrated that ferroptosis can modulate immune responses by promoting the infiltration and activation of TICs, thereby improving the outcomes of immunotherapy. However, ferroptosis in immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) can trigger an "immunosuppressive wave," affecting other immune cells in the tumor immune microenvironment. This demonstrates the dual role of ferroptosis in TNBC therapy, emphasizing the need for a nuanced understanding of its effects on different immune cells and tumor cells. Herein, we further elaborate the role of ferroptosis in TNBC cells and its interactions with tumor-infiltrating immune cells (TICs) within the TME.

Introduction

At present, breast cancer has become one of the most common malignant tumors among women globally, with triple negative breast cancer (TNBC) patients accounting for approximately 15% of all breast cancer patients [1].Compared with other subtypes of breast cancer, TNBC is more aggressive and has a worse prognosis [2]. Owing to the lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2), TNBC does not respond to endocrine therapy or anti-HER-2 molecular targeted therapy [3]. Therefore, chemotherapy is still the primary strategy for TNBC treatment. However, because of the high tumor heterogeneity in TNBC, conventional chemotherapy protocols have limited efficacy, and the residual lesions may eventually lead to recurrence and metastasis [4].

Recent reports indicate that TNBC cells express high levels of programmed death ligand-1 (PD-L1) and have more tumor-infiltrating lymphocytes (TILs) [5]. Notably, TILs have been identified as a robust independent predictor of the efficacy of neoadjuvant chemotherapy in breast cancer [6]. Additionally, increased levels of TILs are significantly associated with prolonged survival in patients with TNBC [7]. These data collectively underpin the potential for immunotherapeutic approaches in TNBC. Concurrently, clinical trials exploring immunotherapy for TNBC are progressively advancing [8]. However, only a small proportion of patients can benefit from current immunotherapy strategies because of tumor heterogeneity and the immunosuppressive tumor microenvironment (TME) [9, 10]. This highlights the urgent need to explore new therapeutic strategies to improve the response rate of TNBC patients to immunotherapy.

Ferroptosis is a new form of programmed cell death, differing from apoptosis, pyroptosis and necroptosis [11]. Recent studies have demonstrated that ferroptosis can not only enhance the efficacy of anthracycline chemotherapy in breast cancer [12, 13], but also increase the sensitivity of breast cancer to radiotherapy [14]. Interestingly, compared with normal human breast epithelial cells, TNBC cells are more sensitive to ferroptosis, which inhibits the growth of TNBC cells [15, 16]. These findings provide novel perspectives for breast cancer therapy, with ferroptosis modulation emerging as a potential therapeutic target, particularly in TNBC. Moreover, ferroptosis has been found to modulate the proliferation, activation, and exhaustion of TICs within the TME, thereby influencing the efficacy of immunotherapy. [17–19]. Given that TNBC exhibits high immunogenicity and TICs levels [20], this study initially elucidates the regulation of ferroptosis by several metabolic networks in TNBC, which is characterized by elevated immunogenicity and TICs levels. Furthermore, the correlation between TNBC cells, ferroptosis, and TICs was examined, along with the potential uses of ferroptosis in overcoming immunotherapy resistance in TNBC (Fig. 1).

Fig. 1.

Schematic illustration of main contents in this review. (1) TNBC cells are particularly sensitive to ferroptosis due to their high lipid and iron content. (2) Ferroptosis, an iron-dependent form of cell death, is regulated by metabolic networks involving iron, glutathione (GSH), and lipid metabolism in TNBC cells. (3) The tumor microenvironment (TME) of TNBC cells contains many tumor-infiltrating immune cells. Ferroptosis of TNBC cells can affect the infiltration level of tumor-infiltrating immune cells, and the secretion of these cells can also affect the sensitivity of TNBC cells to ferroptosis. In addition, the differential susceptibility of various immune cells to ferroptosis underscores the complexity of the TME

Regulatory mechanisms of ferroptosis in TNBC cells

Ferroptosis is a distinct form of cell death caused by iron-dependent lipid peroxidation [11]. It occurs when ferrous iron and lipoxygenases (LOXs) catalyze the peroxidation of unsaturated fatty acids on the cell membrane [21]. TNBC cells, rich in lipids and iron, are particularly sensitive to ferroptosis [22]. Studies have shown that various traditional drugs, novel drugs, new compounds and nanomaterials can increase ferroptosis-mediated cell death in TNBC, suggesting a potential treatment strategy [23–25]. The ferroptosis process in TNBC is dynamic and complex, which is precisely regulated by cellular metabolic networks, including iron metabolism, GSH metabolism, and lipid metabolism (Fig. 2).

Fig. 2.

Overview of the metabolic pathways involved in ferroptosis regulation in TNBC cells, highlighting iron metabolism, glutathione (GSH) metabolism, and lipid metabolism. (1) Iron metabolism: Iron Uptake: Iron enters TNBC cells via transferrin receptor 1 (TFR1) on the cell membrane, which binds to iron-loaded transferrin (TF) or lactoferrin (LF) complexes. Increased expression of TFR1 and iron-saturated lactoferrin (Holo-Lf) enhances intracellular iron levels, promoting ferroptosis. Iron Storage: Intracellular iron is stored as ferritin (FER), composed of two subunits. Overexpression of ferritin heavy chain (FTH) reduces ferroptosis sensitivity, while NCOA4-regulated ferritin autophagy releases iron, enhancing ferroptosis. Iron Export: Ferroportin (FPN) removes iron from TNBC cells. Overexpression of FPN decreases intracellular iron content, thereby reducing ferroptosis. (2) GSH Metabolism: Synthesis: GSH is synthesized from cysteine and glutamate by GCL and GSS. Transport: Cystine uptake via system X_C⁻ (SLC7 A11/SLC3 A2) is essential for GSH synthesis. Reduced SLC7 A11 or SLC3 A2 expression decreases GSH levels, promoting ferroptosis. Redox Regulation: GPX4 converts GSH to GSSG, detoxifying lipid peroxides. Low GPX4 activity/expression increases lipid peroxide accumulation, inducing ferroptosis. (3) Lipid Metabolism: Fatty Acid Uptake: Fatty acids (FAs) enter TNBC cells via the CD36 protein. PUFA Synthesis: Polyunsaturated fatty acids (PUFAs) are synthesized from FAs by FADS1/2. High FADS1/2 expression increases lipid peroxidation and ferroptosis susceptibility. Lipid Storage: PUFAs can be stored in lipid droplets regulated by FABP4, which inhibits ferroptosis. Lipid Peroxidation: Key enzymes involved in lipid peroxide formation include ACSL4, LPCAT3, and LOXs. High ACSL4 expression correlates with ferroptosis sensitivity and TNBC invasiveness

Iron metabolism

A significant feature of ferroptosis is the excessive accumulation of intracellular iron. The modulation of iron transport processes alters the sensitivity of TNBC cells to ferroptosis by altering the labile iron content of cells. Specifically, Fe³⁺ binds with transferrin (TF) or lactoferrin (LF) to form a complex, which enters the cells via transferrin receptor 1 (TFR1) on the surface of the cell membrane. The intracellular iron content can be increased by the increasing expression of TF and Iron-saturated lactoferrin (Holo-Lf), which eventually causes ferroptosis in TNBC cells [14, 26]. Nevertheless, low iron-saturated Lf (Apo-Lf) protects cells from ferroptosis by increasing the expression of Solute Carrier Family 7 Member 11‌ (SLC7 A11) [19]. As for TFR1, it is highly expressed in MDA-MB-231 TNBC cells and correlated with poor prognosis in TNBC patients [27]. The high expression of TFR1 can increase the intracellular iron content, which may be the reason for the sensitivity of TNBC cells to ferroptosis. Ferroportin (FPN) is also involved in iron transport in TNBC cells, removing iron from cells and the overexpression of FPN can reduce ferroptosis of TNBC cells [28]. In addition to the iron transport processes, iron storage also affects ferroptosis in TNBC. Inside the cell, iron is primarily stored as the binding of Fe²⁺ to ferritin (FER) [29, 30]. FER is composed of two structurally similar but functionally different subunits that are overexpressed in breast cancer [31]. But reducing the expression of ferritin heavy chain (FTH) can increase the sensitivity of TNBC cells to ferroptosis [32]. Moreover, NCOA4-regulated FER autophagy leads to the release of iron in cells, which also promotes ferroptosis in TNBC cells [33, 34]. In summary, the regulation of iron metabolism plays a crucial role in modulating ferroptosis in TNBC cells. The balance between iron uptake, transport, and storage is essential for determining the sensitivity of these cells to ferroptosis. Targeting key components of iron metabolism may provide novel therapeutic strategies to enhance ferroptosis in TNBC cells and improve the prognosis of patients. Further research is warranted to fully elucidate the complex interplay between iron metabolism and ferroptosis in TNBC and to explore the potential clinical applications of these findings.

GSH metabolism

GSH is a potent antioxidant that reduces intracellular ROS in TNBC cells and plays a key role in the regulation of ferroptosis. Studies have shown that TNBC has lower GSH levels and higher ROS levels compared with other breast cancer subtypes [35]. These findings indicate that TNBC cells with abnormal GSH metabolism are more susceptible to ferroptosis. GSH is synthesized from cysteine and glutamate under the catalysis of γ-glutamylcysteine ligase (GCL) and glutathione synthetase (GSS) [35]. Cystine is imported into cells via a cystine/glutamate transporter (system X_C⁻), which is composed of SLC7 A11 and solute carrier family 3 (activators of dibasic and neutral amino acid transport), member 2 (SLC3 A2). Reduction of SLC7 A11 expression decreases the uptake of cystine and subsequently reduces the synthesis of GSH, which ultimately triggers ferroptosis in TNBC cells [36]. Similarly, low expression of SLC3 A2 in TNBC cells also leads to ferroptosis [37]. Glutathione peroxidase 4 (GPX4) is the rate-limiting enzyme during ferroptosis [38, 39] and plays an important role in GSH metabolism. Under the catalysis of GPX4, GSH is converted to oxidized glutathione (GSSG) [40–42]. Thus, decreased GPX4 activity or expression can lead to the accumulation of lipid peroxides in TNBC cells, and eventually cause ferroptosis of cells. Notably, human TNBC cells have low expression levels of GPX4, whereas other GPX family members have relatively high expression levels [43, 44]. Therefore, further studies are needed to clarify the expression patterns of various GPX family members in TNBC and their regulatory effects on ferroptosis. In conclusion, ferroptosis in TNBC cells is regulated by GSH generation and degradation. Therefore, inducing ferroptosis by targeting GSH metabolism shows promise for the treatment of TNBC.

Lipid metabolism

The processes of lipid metabolism are finely regulated and associated with ferroptosis. Fatty acids (FAs) enter TNBC cells through the CD36 protein. Polyunsaturated fatty acids (PUFAs) are synthesized from FAs under the catalysis of FADS1/2. TNBC cells with high expression of FADS1/2 are more prone to ferroptosis [45]. This is mainly because phospholipids containing PUFAs are more susceptible to lipid peroxidation. In contrast, monounsaturated fatty acids (MUFAs) regulated by SCD1 are less prone to lipid peroxidation, thereby inhibiting ferroptosis in TNBC cells [46]. Additionally, PUFAs can be stored in lipid droplets regulated by FABP4, which can inhibit ferroptosis in TNBC cells [47]. Collectively, the regulation of lipid synthesis and storage processes can affect the sensitivity of TNBC cells to ferroptosis. The key enzymes in lipid peroxide formation include Acyl-CoA synthetase long chain family member 4(ACSL4), lysophosphatidylcholine acyltransferase 3 (LPCAT3), and lipoxygenases (LOXs) [48]. TNBC shows a high level of ACSL4. Further studies found that ACSL4 can increase the invasiveness of TNBC through membrane phospholipid remodeling [49, 50], indicating that it plays an important role in lipid metabolism. Interestingly, the expression of ACSL4 is correlated with the sensitivity to ferroptosis in TNBC cells [51, 52], and even a small amount of ACSL4 protein could sensitize cells to RSL3-induced ferroptosis [39]. These all partially explain why TNBC cells are more sensitive to ferroptosis and suggest the possibility of targeting ACSL4 to induce ferroptosis in the treatment of TNBC. Unfortunately, little research has been done on LPCAT3 and LOXs in TNBC cells. Although SBFI26 treatment promoted ferroptosis in TNBC cells and increased the expression of LOX12, LOX5, LOX15, and LOXE3 [53], the role of different LOXs in the ferroptosis of TNBC cells still requires further investigation. In summary, lipid peroxidation in TNBC cells is closely linked to lipid metabolism. Regulating lipid metabolism via various enzymes and endogenous metabolites can regulate the ferroptosis process, providing new clinical strategies for treating TNBC.

Effects of ferroptosis on TICs

The tumor microenvironment (TME) in TNBC consists not only of tumor cells but also of immune cells and supporting cells [54, 55]. TICs refer to intratumoral and peritumoral immune cells, which are crucial for the pathogenesis, prognosis, and treatment of TNBC [56–60].

Recently, immunogenic cell death (ICD) has garnered widespread attention as a special mode of cell death, which mainly generates adaptive immune responses against antigens released by dying cells, especially cancer cells undergoing death [61]. Specifically, damage-associated molecular patterns (DAMPs), such as high mobility group box 1 protein (HMGB1), and pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), which are released during the process of cancer cell death can be recognized by pattern recognition receptors (PRRs). This recognition induces an immune response, thereby promoting to anti-tumor immunity [62]. Recent advances have indicated that ferroptosis, a form of ICD, can elicit an immune response and regulate tumor growth, thereby playing a crucial role in anti-tumor immunity [63]. In addition, ferroptosis has been reported to be involved in the differentiation, activation, trafficking, and functional regulation of immune cells in the TME [64, 65]. Considering that TICs play different roles in TNBC, we further elaborate the relationship between ferroptosis and TICs in TNBC and explore the implications of ferroptosis-targeted therapy in the treatment of TNBC (Fig. 3).

Fig. 3.

The relationship between ferroptosis and TICs in TNBC cells. TNBC cells undergoing ferroptosis elicit an immune response by releasing DAMPs and tumor-associated antigens (TAAs). Specifically, this process promotes the maturation of DCs, enhancing their antigen presentation ability and leading to the infiltration of CD4 + T and CD8 + T cells. In turn CD8 + T cells promote ferroptosis in TNBC cells by secreting IFN-γ. Additionally, IFN-γ promotes the repolarization of TAMs to the M1 phenotype, which exerts an anti-tumor effect. Moreover, hydrogen peroxide generated during the repolarization process further enhances ferroptosis in TNBC cells

Tumor Infiltrating Lymphocytes (TILs)

TILs are mainly composed of T cells and B cells, which are directly or indirectly involved in the immune response and influence the growth and treatment response of TNBC [66, 67]. In recent years, increasing evidence has shown that TILs can induce ferroptosis in tumor cells [68]. Therefore, elucidating the role of ferroptosis in TILs and exploring its therapeutic potential in TNBC is of great significance.

T cells

T cells play a central role in anti-tumor immunity. They are mainly categorized into subsets: helper T cells (CD4 + T cells), cytotoxic T cells (CD8 + T cells) and regulatory T cells (Tregs) [69].

CD4 + T cells have the capacity to differentiate into Th1, Th2, Th9, Th17, and Tfh subsets, influenced by regulatory factors such as antigens and cytokines [70]. A study found that a TNBC ferroptosis-related gene signature is associated with the infiltration of CD4 + T cells [71]. Liu et al. further confirmed this view [72]. TNBC cells undergoing ferroptosis release DAMPs, which cause a strong immune response and significantly increase CD4 + T cell infiltration in the TME [72]. Given that CD4 + T cell infiltration can trigger immune responses, it may be possible in the future to enhance antitumor efficacy by targeting ferroptosis in TNBC cells to promote the infiltration of cytotoxic CD4 + T cells.

As the main executors of anti-tumor immunity in the TME, CD8 + T cells are closely related to the therapeutic effect and prognosis of TNBC. Studies have shown that a ferrocene-containing Ir(III) photosensitizer (IrFc1) can induce ferroptosis in TNBC cells, subsequently increasing CD8 + T cells infiltration [73]. Further studies found that ferroptosis of TNBC cells not only increased the infiltration of CD8 + T cells, but also enhanced their secretion of Interferon-γ (IFN-γ), contributing to anti-tumor immune effects [72]. Interestingly, IFN-γ secreted by CD8 + T cells can promote ferroptosis of TNBC cells [74, 75]. Thus, there may be a positive feedback effect between ferroptosis of TNBC cells and CD8 + T cells, which further amplifies the anti-tumor effect. Mechanically, IFN-γ inhibits cystine uptake in cancer cells by down-regulating the expression of SLC3 A2 and SLC7 A11, which eventually leads to ferroptosis of cells [76]. However, given the tumor heterogeneity, whether this mechanism is the same in TNBC needs further verifications. Ye et al. demonstrated that metformin reduces T-cell exhaustion and increases the infiltration of activated CD8 + T cells [77]. Activated CD8 + T cells could significantly amplify ferroptosis by increasing intracellular L-glutamine content in TNBC cells [77]. This further confirmed the role of GSH metabolism in ferroptosis of TNBC cells, and the mechanism of L-glutamine regulation by immune cells needs to be further explored.

Currently, most of studies suggest that ferroptosis in TNBC cells, as an ICD, can trigger the infiltration of CD4 + and CD8 + T cells in the TME, thereby improving the efficacy of anti-tumor immunotherapy. Therefore, this mechanism may be a potential strategy to improve the efficacy of immunotherapy in TNBC patients in the future. However, studies mainly focus on the effect of ferroptosis in TNBC cells on tumor-infiltrating T cells but ignore the effect of ferroptosis in tumor-infiltrating T cells on TNBC cells. Some studies have confirmed that the overexpression of GPX4 in CD8 + T cells can increase their number in the TME, and targeting GPX4-induced ferroptosis in CD4 + T cells and Tregs has a significant effect on anti-tumor immunity [78, 79]. Despite the potential of ferroptosis to enhance antitumor immunity, the roles of Tregs in ferroptosis induction and the implications of ferroptosis in TNBC cells on Tregs infiltration remain underexplored. While Tregs are known to exert immunosuppressive effects in the TME [80, 81], and ferroptosis of tumor cells can reduce Tregs infiltration [78, 82], substantial research gaps exist in understanding these interactions specifically within TNBC. Han et al. discovered that tumor cells outcompete T cells in cystine uptake due to the high expression of SLC7 A11 [83]. This competition induces T cell exhaustion and ferroptosis, thereby diminishing T cell anti-tumor function [83]. Whether inducing ferroptosis in Tregs and inhibiting ferroptosis in CD4 + T cells and CD8 + T cells can alleviate the immunosuppressive TME in TNBC needs to be further explored.

B cells

There are many subsets of B cells in the TME, including regulatory B cells (Bregs), plasma cells and memory B cells. In TNBC, activated Tfh cells can stimulate B cells to become plasma cells, which promotes the secretion of antibodies to generate anti-tumor immunity [84, 85]. Unfortunately, studies on how ferroptosis affects B cells in TNBC are limited. Some studies have shown that different subtypes of B cells exhibit varying sensitivities to ferroptosis [86]. Wang et al. reported that neutrophils secrete IL-6, which prevents B cells from undergoing ferroptosis via the IL-6/STAT3/SLC7 A11 pathway [87]. This pathway is crucial for regulating GSH metabolism, as IL-6 activates STAT3 [87], which in turn upregulates SLC7 A11 to enhance cystine uptake and GSH synthesis, thereby inhibiting ferroptosis. These findings suggest that the regulation of GSH metabolism in the TME may influence the sensitivity of B cells to ferroptosis. Therefore, the interaction between B cells and ferroptosis may provide new perspectives for the treatment of TNBC in the future.

Natural killer (NK) cells

NK cells, crucial to the innate immune system, activate the adaptive immune system by releasing cytokines and chemokines [88]. Lin et al. reported that the expression of ferroptosis-related gene PRNP is negatively correlated with NK CD56 bright cells in TNBC [89]. However, there is currently no direct evidence that TNBC cells undergoing ferroptosis can promote the infiltration of NK cells in the TME. Ideally, considering that NK cells can exert an anti-tumor effect, ferroptotic TNBC cells promote NK cells infiltration, and NK cells exert their antitumor effects, but these effects remain poorly studied. Exploring this interaction could unveil new therapeutic targets and improve outcomes for TNBC patients. In addition, the levels of ferroptosis-related and lipid oxidation-related proteins are increased in NK cells [90]. More importantly, it has been found that inhibiting ferroptosis in NK cells can enhance anti-tumor effects [91]. Thus, future strategies may focus on protecting NK cells from ferroptosis by modulating lipid metabolism, thereby restoring their anti-TNBC capabilities. Interestingly, some studies have found that the level of cytotoxic NK cells is relatively high in TNBC at baseline, similar to normal breast epithelial tissue [85]. This observation suggests that TNBC patients may not benefit significantly from NK cell–targeted therapies. Therefore, the feasibility of regulating NK cells by targeted inhibition of ferroptosis in TNBC to exert anti-tumor effects also needs to be further investigated.

Tumor-associated macrophages (TAMs)

TAMs play a key role in regulating the interaction between the immune system and cancer. Under the influence of various cytokines, macrophages differentiate into M1 and M2 TAMs [92, 93]. Ferroptotic TNBC cells elicit an immune response, which promote the transformation of M2 TAMs to M1 TAMs, thereby inhibiting the growth of TNBC [94]. While ferroptosis in TNBC cells promotes the phenotypic transformation of TAMs, the peroxides generated in the process of repolarization further regulate ferroptosis in TNBC cells [95]. Given the role of M2 TAMs in facilitating tumor progression and M1 TAMs in anti-tumor effects, future strategies may focus on promoting the differentiation of M2 TAMs to M1 TAMs by targeting ferroptosis in TNBC cells, thereby rescuing the immunosuppressive TME. However, there are few studies describing the effect of ferroptosis in TAMs upon TNBC cells. Studies have found that different types of TAMs exhibit varying sensitivities to ferroptosis. For example, M2 TAMs are more prone to ferroptosis due to the lack of inducible nitric oxide synthase (iNOS) [96]. Further studies are needed to confirm whether this phenomenon holds true in TNBC. In addition, IL-6 produced by TNBC cells can induce TGF-β1 secretion by TAMs. The IL-6-TGF-β1 axis activates hepatic leukemia factor (HLF), which increases ferroptosis resistance in TNBC cells by activating GGT1 [97]. In the context of TNBC, inducing ferroptosis of M2 TAMs to reduce the secretion of TGF-β1 and inhibiting ferroptosis of M1 TAMs may help to improve the immunosuppressive TME and enhance the anti-tumor effect.

Dendritic cells (DCs)

DCs, the primary antigen-presenting cells in the innate immune system, play a crucial role in eliciting anti-tumor immunity [98]. TNBC cells undergoing ferroptosis may promote the infiltration and maturation of DCs by releasing DAMPs [99]. Specifically, DCs induce anti-tumor immunity by recognizing TAAs and exerting antigen-presenting functions [100]. Interestingly, Wiernicki et al. reported that co-culture of"initial"ferroptotic cancer cells with DCs inhibited the maturation of DCs, limiting their antigen cross-presentation capabilities [101]. Therefore, the conditions under which ferroptosis of TNBC cells promotes DC maturation require further investigation. Studies have shown that lipid metabolism- related gene PPARG can induce ferroptosis in DCs, which impairs their maturation and exacerbates the immunosuppressive TME [102]. In addition, DCs containing high lipid level exhibit a reduced ability for antigen processing [103]. In the future, inhibiting ferroptosis of DCs by regulating lipid metabolism may enhance their antigen presentation ability, thereby improving the effect of immunotherapy for TNBC. However, this therapeutic approach needs further confirmation, and the underlying molecular mechanisms require additional investigation.

Myeloid-derived suppressor cells (MDSCs)

A group of immature and heterogeneous cells constitute MDSCs that play a crucial role in expanding immunosuppressive network in the TME [104]. MDSCs limit the efficacy of IFN-γ and facilitate the progression of TNBC, whereas restriction of MDSCs can enhance antitumor immunity in TNBC [105, 106]. Although high expression of ferroptosis-related gene SLC35 A2 in TNBC cells is associated with MDSCs infiltration [107], there is still no evidence that ferroptosis of TNBC cells can reverse the immunosuppressive TME by reducing the infiltration of MDCSs. In addition, N-acylsphingosine amide hydrolase (ASAH2) promotes MDSCs survival and accumulation by inhibiting ferroptosis, and the use of ASAH2 inhibitors in TNBC can inhibit tumor growth [108]. Thus, inducing ferroptosis in MDSCs can theoretically eliminate the immunosuppressive component in the TME. It should be noted that inducing ferroptosis in MDSCs may inadvertently lead to ferroptosis in other TICs with anti-tumor activities due to the immunosuppressive wave effect. Specifically, ferroptosis can transform neutrophils into polymorphic nuclear neutrophil myeloid-derived suppressor cells (PMN-MDSCs). In the TME, PMN-MDSCs are sensitive to ferroptosis and can undergo ferroptosis spontaneously. Lipid peroxidation products from PMN-MDSCs during the process of ferroptosis not only directly suppress T cells function, but also induce ferroptosis in M2 TAMs, exacerbating the immunosuppressive TME [103, 109–111]. Contrary to the conventional wisdom, inducing ferroptosis in these immunosuppressive cells instead exacerbates the immunosuppressive TME. Therefore, considering the existence of different types of MDSCs, the application of ferroptosis therapies targeting MDSCs is complex, and further exploration is needed to prove their feasibility in the treatment of TNBC.

Conclusion

This review has comprehensively elucidated the metabolic networks of ferroptosis in TNBC cells and its interactions with various TICs within the TME. Ferroptosis, a form of iron-dependent cell death, has emerged as a promising therapeutic strategy for TNBC due to its potential to enhance anti-tumor immunity. However, the impact of ferroptosis on different types of immune cells and their subsequent effects on TNBC cells are highly context-dependent and multifaceted. TNBC cells undergoing ferroptosis release DAMPs and TAAs, which can promote the maturation and infiltration of DCs and T cells, thereby enhancing anti-tumor immunity. For instance, ferroptosis-induced infiltration and activation of CD8 + T cells, which secrete IFN-γ, can further sensitize TNBC cells to ferroptosis, creating a positive feedback loop that amplifies tumor suppression. Additionally, ferroptosis can repolarize TAMs from the immunosuppressive M2 phenotype to the anti-tumor M1 phenotype, thereby alleviating immune suppression within the TME. The differential susceptibility of various immune cells to undergo ferroptosis underscores the complexity of the TME. For instance, while ferroptosis in MDSCs can reduce their immunosuppressive functions, it may also inadvertently trigger an"immunosuppressive wave,"leading to ferroptosis in other immune cells with anti-tumor activities and further exacerbating the immunosuppressive TME. This dual effect highlights the need for a nuanced understanding of the interplay between ferroptosis and immune cell functions.

In conclusion, ferroptosis holds dual-edged potential in TNBC therapy. Future studies should explore combination therapies that synergize ferroptosis with immunotherapy and identify biomarkers to predict therapeutic responses. A comprehensive understanding of the differential effects of ferroptosis on various TICs will be crucial for optimizing ferroptosis-targeted therapies and improving outcomes for patients with TNBC. By selectively inducing ferroptosis in TNBC cells and immunosuppressive components of the TME through metabolic networks, while preserving the function of tumor-suppressive TICs, we can enhance anti-tumor immunity and improve therapeutic outcomes. Future research should focus on elucidating the dynamic regulation of ferroptosis within the TME and developing precision therapeutic strategies to maximize its tumor-suppressive effects while minimizing potential drawbacks. Such approaches may pave the way for innovative and effective treatments for TNBC.

Author contributions

Lining Hu and Jiejie Hu wrote the main manuscript text and Chengdong Qin and Siyuan Liu prepared Figs. 1–3.Yang Yu provided ideas for this article.

Funding

This work was funded by the Traditional Chinese Medicine Science and Technology Plan Program of Zhejiang Province, 2022ZB005

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, and all authors report no conflicts of interest in this work.