Co-targeting ferroptosis and immune evasion through small molecules in breast cancer
-
Jianbo Zhou
,
Cheng Peng
Abstract
Breast cancer accounts for the highest proportion of cancer cases among women worldwide. Despite remarkable advances in cancer diagnosis and treatment, novel precision therapy strategies for various subtypes of breast cancer are urgently needed. Ferroptosis, which is different from programmed cell death, such as apoptosis, necrosis, and pyroptosis, is considered an alternative method for cancer therapy. A comprehensive understanding of ferroptosis in breast cancer is lacking, including, but not limited to, ferroptotic inducers (small molecule drugs and natural products) and the interaction between ferroptosis and immunotherapy. Induction of ferroptosis is recognized as a novel and promising strategy for cancer pharmacotherapy, and a comprehensive understanding of the role of ferroptosis in breast cancer could help provide alternative treatment strategies for breast cancer. Furthermore, we highlight the signaling crosstalk bridging ferroptosis with the immune microenvironment and the feasibility of targeting their potential regulators (e.g., STAT3, AR, EZH2, and PRMT5) using small molecules to simultaneously achieve the induction of ferroptosis and inhibition of immune escape.
Introduction
Despite of encouraging advancements in prevention and treatment of breast cancer in recent years, its incidence and mortality remain alarmingly high. Breast cancer is the most prevalent type of among newly diagnosed cases in women, accounting for 11.7% of all cancer diagnoses globally.[1,2] The latest epidemiological statistics of breast cancer imply that nearly one-third of newly diagnosed cancers in women is breast cancer, comprising 14% of cancer-related deaths among them.[3] Recent data indicate that the diagnosis and mortality rate for breast cancer is 30% and 22%, respectively in the United States in 2021.[4] Furthermore, a trend of younger patients being diagnosed with breast cancer deserves concern.[5] Breast cancer can be classified into three histological subtypes based on the expression status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2): luminal (positive for ER and/or PR, HER2 negative), HER2+ (HER2 positive), and triple-negative breast cancer (TNBC; negative for HER2, ER, and PR). The luminal subtype can be further divided into luminal A (low Ki-67 expression) and luminal B (high Ki-67 expression) based on Ki-67 levels.[6,7] TNBC is more frequently observed in younger patients and is typically associated with larger tumor size, higher grade, and a greater likelihood of lymph node involvement at diagnosis, demonstrating increased biological aggressiveness.[8] Women with TNBC also experience higher early distant recurrence rates and worse five-year survival outcomes than those with other breast cancer subtypes.[8,9]
In 2011, Lehmann et al. performed gene expression profiling on tumor samples originating from 587 patients with TNBC with six molecular subtypes identified, say, basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M), mesenchymal stem-like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR).[10] In 2015, Matthew et al.[9] analyzed RNA and DNA collected from 198 TNBC tumors at Baylor College of Medicine and distinguished four subtypes: luminal androgen receptor (LAR), mesenchymal (MES), basal-like immunosuppressed (BLIS), and basal-like immune-activated (BLIA).[11] In 2016, an integrative study of TNBC by Shao Zhimin and his colleagues from Fudan University who revealed significant heterogeneity in molecular characteristics, metabolic reprogramming, and tumor microenvironment (TME) proposed a classification system for TNBC that includes four subtypes, known as the Fudan University Shanghai Cancer Center (FUSCC) classification: mesenchymal-like (MES), luminal androgen receptor (LAR), immunomodulatory (IM), basal-like and immune-suppressed (BLIS) subtypes.[9]
Although PARP inhibitors have been approved for treating poly (adenosine diphosphate–ribose) polymerase (BRCA)-mutated triple-negative breast cancer (TNBC),[12] targeted therapies for TNBC remain the leading therapies in the early stages, with chemotherapy being the sole standard treatment for non-metastatic TNBC.[13,14] Neoadjuvant chemotherapy (NAC) refers to chemotherapy administered before surgery or radiation therapy, benefiting patients with locally advanced disease through reducing tumor size and increasing the likelihood of breast-conserving surgery.[15,16] NAC shows significantly better efficacy for TNBC subtypes compared to estrogen receptor-positive breast cancer, thereby improving the prognosis of TNBC patients. Preferred chemotherapy regimens for TNBC include combination therapies such as paclitaxel/ docetaxel plus doxorubicin plus cyclophosphamide, docetaxel plus cyclophosphamide, doxorubicin plus cyclophosphamide, and cyclophosphamide plus methotrexate plus fluorouracil.[17,18] While there are currently no universally accepted biomarkers to predict response to NAC, evidence derived from multi-omics or tumor immune microenvironments may serve as potential indicators, including but not limited to proteomic, genomic, and transcriptomic features, as well as non-coding RNAs.[19,20] The introduction of neoadjuvant chemo-immunotherapy has transformed the treatment landscape for TNBC, although challenges such as patient stratification, management of drug toxicity, and identification of biomarkers still remain.[21] Identifying candidate small molecules can provide alternative options for chemotherapy for the treatment of TNBC. Searching for effective and low-toxicity candidate molecules from natural products may be a promising approach.[22, 23, 24, 25, 26]
Ferroptosis, an emerging and novel mechanism of cell death, was discovered and defined in 2012, a programmed cell death driven by iron-dependent lipid peroxidation. This may provide new therapeutic opportunities against cancers refractory to conventional therapies, and is considered a new cancer treatment strategy. It is also an important mechanisms in cancer therapies, such as radiotherapy, immunotherapy, chemotherapy, and targeted therapy.[27] This concept has aroused great interest among researchers, and numerous studies have successively discovered distinct ferroptosis regulatory mechanisms and key modulators (Figure 1). The corresponding literature reports are increasing annually, with approximately 7000–9000 ferroptosis-related studies likely to be published in 2025.[28,29] However, the potential interactions between ferroptosis and immunotherapy in breast cancer, as well as pharmacological options targeting ferroptosis in breast cancer, remain poorly understood.
![Figure 1 Timeline of ferroptosis and publication trends. The upper part of the figure outlines the timeline of significant discoveries of ferroptosis. The lower graph depicts the number of published articles indexed in the PubMed database under the keyword “Ferroptosis”. The concept of ferroptosis was first introduced in 2012;[30] glutathione peroxidase 4 (GPX4) was identified as a key inhibitor of ferroptosis in 2014;[31] the mechanism by which acyl-CoA synthetase long chain family member 4 (ACSL4) induces ferroptosis was elucidated in 2016;[32] BECN1 was shown to inhibit the functionality of solute carrier family 7 member 11 (SLC7A11) in 2018;[33] GPX4-independent anti-ferroptotic system involving guanosine triphosphate cyclohydrolase-1 (GCH1)/BH4 (tetrahydrobiopterin) was discovered in 2020;[34] Nuclear factor erythroid 2-related factor 2 (NRF2) was found to transcribe ferroptosis suppressor protein 1 (FSP1), promoting resistance to ferroptosis in 2022;[35] 7-dehydrocholesterol (7-DHC) was identified as an endogenous inhibitor of ferroptosis in 2024.[36]](/document/doi/10.1515/jtim-2025-0093/asset/graphic/j_jtim-2025-0093_fig_001.jpg)
Timeline of ferroptosis and publication trends. The upper part of the figure outlines the timeline of significant discoveries of ferroptosis. The lower graph depicts the number of published articles indexed in the PubMed database under the keyword “Ferroptosis”. The concept of ferroptosis was first introduced in 2012;[30] glutathione peroxidase 4 (GPX4) was identified as a key inhibitor of ferroptosis in 2014;[31] the mechanism by which acyl-CoA synthetase long chain family member 4 (ACSL4) induces ferroptosis was elucidated in 2016;[32] BECN1 was shown to inhibit the functionality of solute carrier family 7 member 11 (SLC7A11) in 2018;[33] GPX4-independent anti-ferroptotic system involving guanosine triphosphate cyclohydrolase-1 (GCH1)/BH4 (tetrahydrobiopterin) was discovered in 2020;[34] Nuclear factor erythroid 2-related factor 2 (NRF2) was found to transcribe ferroptosis suppressor protein 1 (FSP1), promoting resistance to ferroptosis in 2022;[35] 7-dehydrocholesterol (7-DHC) was identified as an endogenous inhibitor of ferroptosis in 2024.[36]
Overview of ferroptosis
Stockwell et al. first proposed the concept of ferroptosis in 2012, defining it as a type of programmed cell death characterized by the accumulation of iron-dependent lipid peroxides, distinct from apoptosis.[30] The triggering of ferroptosis is critically linked to iron ions, which drive the peroxidation of polyunsaturated fatty acids (PUFAs). The overloading and buffering capacity of ferroptotic defense mechanisms will cuase the lethal accumulation of lipid peroxides in cellular membranes resulting in subsequent membrane rupture and cell death as ferroptosis.[27] Ferroptosis is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. Unique with multiple forms of regulated cell death, ferroptosis does not require caspases (mediators of apoptosis and pyroptosis), ATP depletion or mitochondrial reactive active oxygen (ROS) generation (mediators of necrosis), Bax/Bak (regulators of the mitochondrial membrane potential), or elevated intracellular Ca2+ level. Consequently, a combination of specific biomarkers can differentiate ferroptosis from other modes of cell death, including but not limited to lipid peroxides, mitochondrial morphology, and gene expression (e.g., SLC7A11 and ACSL4).[38] The mechanisms that modulate or trigger ferroptosis involve lipid metabolism, antioxidant defense systems, and iron metabolism (Figure 2). Here, we collected recent studies involving the above three ferroptotic signaling pathways to shed light on the detailed molecular modulation of ferroptosis in breast cancer (Figure 3).
The core pathways of ferroptosis. The antioxidant mechanisms (filled by blue), lipid metabolism (filled by green), and iron metabolism (filled by orange). GSH: glutathione; GSSG: oxidized glutathione; Fe: iron ions; NO: nitric oxide. PUFA: polyunsaturated fatty acids; PUFA-CoA: PUFA with acetyl-CoA; PUFA-PL: phospholipid containing polyunsaturated fatty acid chain; PUFA-PL-OOH: PUFA phospholipid hydroperoxides; MUFA: monounsaturated fatty acyl; MUFA-CoA: MUFA with acetyl-CoA; CoQ10: Coenzyme Q10/ubiquinone; CoQ10H2: reduced CoQ10/Ubiquinol.
Signaling modulation of ferroptosis in breast cancer. The antioxidant mechanisms (filled by blue), lipid metabolism (filled by green), iron metabolism (filled by orange), and the regulatory mechanisms of SLC7A11/GPX4 axis (filled by gray) in breast cancer. CTH: cystathionine γ-lyase; SLC3A2, solute carrier family 3 member 2; ALOX: lipoxygenase; USP: ubiquitin-specific protease; Nrf2, nuclear factor erythroid 2-related factor 2; FSP1: ferroptosis suppressor protein 1; DMT1: divalent metal transporter 1; STEAP3: six-transmembrane epithelial antigen of prostate 3; LPCAT3: lysophosphatidylcholine acyltransferase 3; HMOX1/HO-1: heme oxygenase 1; HIF1α: hypoxia-inducible factor-1; Ub: ubiquitination.
Lipid metabolism
Lipid peroxidation is a free radical-driven reaction that involves unsaturated fatty acids within the cell membrane. The products of lipid peroxidation include initial lipid peroxides (LOOHs) and subsequent reactive aldehydes, such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). Fatty acids are categorized into three types: saturated fatty acids with no double bonds, monounsaturated fatty acids (MUFA), and PUFA that characterized by multiple double bonds.[39] ACSL4 and LPCAT3 were the first proferroptotic factors identified to be involved in the activation of PUFAs particularly represented by arachidonic acid (AA),[38] and their incorporation into cellular membrane lipids.[32] Furthermore, ACSL4 drives ferroptosis through the accumulation of oxidized phospholipid components, particularly phosphatidylethanolamine (PE).[32] Unlike the classic ferroptosis driver, PUFAs, diacyl-PUFA phosphatidylcholines (PC-PUFA) have also been reported to induce ferroptosis, which interacts with the mitochondrial electron transport chain to generate ROS that initiate lipid peroxidation and subsequently induce ferroptosis.[40] The metabolism of PUFAs driven by ACSL4 increases cell sensitivity to ferroptosis, whereas ACSL3-dependent MUFA metabolism inhibits ferroptosis by competing with PUFAs for binding with membrane phospholipids.[41] E-cadherin upregulates the expression of ACSL4 through the Merlin-Hippo-YAP signaling pathway, thereby indirectly influencing ferroptosis sensitivity.[42]
Owing to the metabolic abnormalities of PUFAs in basal-like breast tumors, targeting polar metabolomics to induce ferroptosis has been regarded as a potential therapeutic strategy.[43] Recently, fatty acid desaturases 1 and 2 (FADS1/2) have been shown to modulate ferroptosis sensitivity by facilitating PUFA biosynthesis in TNBC.[44] In addition, SBFI26 upregulates the ferroptosis-driving factor HMOX1 and ALOX12 to accelerate lipid peroxidation in TNBC cells.[45] Interestingly, the long non-coding RNA (lncRNA) Lnc-FASA increases the sensitivity and susceptibility of TNBC cells by inhibiting the peroxidase activity of the anti-ferroptotic protein PRDX1 in a liquid-liquid phase separation manner.[46] The phosphatase pyruvate dehydrogenase phosphatase 2 (PDP2) dephosphorylates ACSL4 to suppress ferroptosis in the luminal-A breast cancer.[47]
Ferroptosis defense systems
There are three cellular defense mechanisms (antioxidant mechanisms) against ferroptosis: the SLC7A11/GSH/ GPX4 system, FSP1/CoQH2 (ubiquinol) signaling, and GCH1/BH4 axis, and all of them are based on the elimination of ROS and lipid peroxides to abrogate ferroptosis.[48] The SLC7A11/GSH/GPX4 axis is the most extensively studied and established anti-ferroptotic signaling pathway. GSH functions as a crucial cofactor for the activity of GPX4 enzyme in eliminating ROS, whereas cysteine is the rate-limiting precursor required for GSH synthesis.[49] Generally, cancer cells take up extracellular cysteine through the cystine-glutamate antiporter system xc-, which facilitates the uptake of cystine (the oxidized dimer of cysteine). In this process, SLC7A11 serves as one of the two transport protein subunits of system xc-, participating in the transmembrane transport of cystine.[50] GPX4 catalyzes the reduction of lipid peroxides, including polyunsaturated fatty acid peroxides (PUFA-OOH) and phospholipid peroxides (PL-OOH)[51] and converts them into their corresponding lipid alcohols. This prevents the accumulation of lipid peroxides, thereby averting membrane rupture and the subsequent onset of cellular ferroptosis.[27] Although the SLC7A11-GSH-GPX4 axis is thought to be a critical mechanism for intracellular ferroptosis defense, certain cancer cell lines remain resistant to ferroptosis even after GPX4 inactivation,[52] indicating the existence of alternative defense mechanisms that are GPX4-independent.[48]
BRCA1, a gene with prevalent mutation in breast cancer, promotes GPX4 ubiquitination and degradation; a GPX4 inhibitor exhibits synergistic efficacy against breast cancer together with a BRCA inhibitor.[53,54] USP11 stabilizes PGAM5 by preventing PGAM5 ubiquitination, and PGAM5 inhibits ferroptosis via SLC7A11/GPX4 and Keap1/Nrf2 axis.[55] Prostaglandin E receptor 3 (PTGER3), a tumor suppressor in TNBC, downregulates GPX4 and PI3K-AKT axis to enhance ferroptosis sensitivity.[56] KCTD10 and USP 18 are responsible for the ubiquitination-dependent degradation and de-ubiquitination-dependent stability of SLC7A11, respectively.[57] Likewise, the deubiquitinase OTUD5, which is inhibited by paclitaxel, stabilizes SLC7A11 through deubiquitination, maintaining paclitaxel resistance in TNBC.[58] USP4 deubiquitinates CARM1 to maintain CARM1-mediated SLC7A11 stability.[59] The deubiquitinase USP35 inhibits ferroptosis via deubiquitinating and stabilizing bromodomain protein 4 (BRD4): the “reader” of histone acetylation, upregulating SLC7A11 in ER+ breast cancer;[60] BRD4 inhibition also decreases GPX4 protein expression.[61] Interestingly, Nrf2/SLC7A11 and p53/SLC7A11 are negatively regulated by theWEE1/SETDB1/Histone 3 lysine 9 trimethylation (H3K9me3, a transcription blockade marker in epigenetics) axis.[62,63]
Acidosis, a hallmark of the tumor microenvironment, causes ferroptosis in breast cancer cells in a ZFAND5/SLC3A2-dependent manner. Additionally, it induces an adverse TME through promoting M1 macrophage polarization in breast cancer.[64] Inhibition of CDK4/6 suppresses the transcription factor SP1 to decrease SLC7A11 expression in luminal-A breast cancer cells.[65] Suppression of GPX4 enhances the sensitivity of ER+ breast cancer cells to the CDK4/6 inhibitor (palbociclib) by promoting the peroxisome AGPAT3, instead of ACSL4.[66] Additionally, the RNA binding protein fragile X mental retardation protein (FMRP) prevents ferroptosis in breast cancer cells and maintains the mRNA stability of SLC7A11 via mediating m6A modification and interacting with splicing factor hnRNPM.[67,69] Another RNA-binding protein, Hu antigen R (HuR), stabilizes SLC7A11 mRNA; its inhibition mediated by the small molecule inhibitor KH-3 triggers ferroptosis in breast cancer cells.[70] Additionally, the RNA-binding protein ILF3 augments CEP55 mRNA stability to upregulate SLC7A11 and GPX4;[11] however, more evidence is needed to decipher how CEP55 influences SLC7A11/GPX4 in cancer biology. Interestingly, LRP8 (ApoER2) facilitates ferroptotic resistance through promoting the translation of GPX4 in a ribosome-dependent manner.[72]
Downregulation of cytokine-like protein 1 (CYTL1) observed in breast cancer tumor tissues, promotes the biosynthesis of anti-ferroptotic metabolite cysteine through the Nrf2/Keap1/cystathionine β-synthase (CBS) pathway axis.[73] EGR1, a tumor suppressor downregulated in breast cancer, promotes erastin-induced ferroptosis by activating the Nrf2-HMOX1 signaling axis.[74] Conversely, the oncogenic MAGEA6 facilitates the AMPK/SLC7A11 axis to improve the sensitivity of TNBC cells to doxorubicin.[75] HMGB3, abnormally expressed in various solid carcinomas, upregulates the expression of anti-ferroptotic proteins (SLC7A11, GPX4, and SLC3A2).[76] In addition, the CoQ10 synthase UBIAD1 (COQ2) enhances ferroptotic sensitivity by decreasing GPX4 and FSP1 expression in breast cancer cells.[77] The farnesoid X receptor (FXR), a scavenger of lipid peroxidation, competitively prevents CREB binding protein (CBP) from binding p53 and subsequent p53 acetylation, which attenuates ferroptosis sensitivity by downregulating the p53/SLC7A11 axis.[78] Cystatin SN (CST1) maintains GPX4 activity via inhibiting GPX4 ubiquitination;[79] FLT3 is reported as a ferroptosis suppressor;[80] while TFAP2C transactivates CST1 and FLT3 to block ferroptosis.[81] The glycolytic enzyme enolase 1 (ENO1) positively regulates CST1 and activates mTOR signaling, connecting glycolysis and ferroptosis.[82] Similarly, a phenomenon involving SLC12A5 mediating the crosstalk between glucose metabolism and ferroptosis is also observed.[83] Another research involving glycolytic the enzyme IDH2 shows that SENP1 stabilizes SIRT3 through de-SUMOylation, maintaining the anti-ferroptotic activity of the SIRT3/IDH2/GSH.[84] Given the crucial role of crosstalk between cellular metabolism and ferroptosis in carcinomas,[85] we look forward to further studies focusing on this direction.
Iron metabolism
Iron metabolism is fundamental to the process of ferroptosis; it encompasses the uptake, utilization, storage, and efflux of iron ions.[86] Iron ions are internalized into cells via the binding of transferrin (iron-containing transferrin, TF) to transferrin receptors (TFR/TFRC), followed by endocytosis of the transferrin complex.[87] Regarding iron storage, various cellular processes regulate the cell susceptibility to ferroptosis by modulating the labile iron pool (LIP). An increase in the intracellular LIP can directly or indirectly generate ROS, leading to the lipid peroxidation and eventually triggering ferroptosis.[88] Additionally, the intracellular LIP can produce free radicals, such as hydroxyl radicals, through Fenton reactions, contributing to the peroxidation of phospholipids.[89]
Autophagy also promote ferroptosis by degrading ferritin, an iron storage protein in cancer cells, which is defined as ferritinophagy.[90] Thus, the autophagic modulators nuclear receptor coactivator 4 (NCOA4) and glutamate oxaloacetate transaminase 1 (GOT1) can increase or decrease LIP in an autophagy-dependent manner.[86,91] Hypoxia-inducible factor 1-alpha (HIF1α) is the upstream transcriptional factor of TFRC, connecting ferroptosis and chemoresistance in breast cancer.[92] ERBB2-driven cell motility 1 (MEMO1) exhibits a pattern similar to that of iron-containing extradiol dioxygenases in terms of binding and carrying iron, suggesting that MEMO1 is a potential iron transporter in breast cancer.[93] Pro-ferroptotic role of PDGFA-associated protein 1(PDAP1) is associated with elevated lysosomal autophagy.[94]
Regulation of ferroptosis
Several transcription factors (P53, NFE2L2/NRF2, ATF3, ATF4, YAP 1, and HIF1α) modulate ferroptosis sensitivity by translationally regulating various ferroptosis-promoting or ferroptosis-suppressing proteins.[95] Additionally, epigenetic mechanisms influence ferroptosis sensitivity by affecting transcription factor activity and post-transcriptional regulatory mechanisms, including chromatin remodeling, non-coding RNAs, histone modifications, and DNA methylation.[96]
Interestingly, ferroptosis is considered to be autophagy-dependent. The autophagy receptor SQSTM1/p62 facilitates degradation of the iron export protein ferroportin 1 (FPN1) in lysosomes, leading to the accumulation of intracellular iron ions, which promotes ferroptosis.[95] Moreover, RAB7A-mediated lipophagy enhances lipid peroxidation in iron-deficient anemia.[97] The inhibition of SLC7A11 mediated by BECN1 results in GSH depletion and subsequent ferroptosis. The expression and release of cathepsin B (CTSB) mediated by STAT3 facilitates lysosome-dependent ferroptosis, while HSP90 enhances the stability of LAMP2A, which supports the degradation of GPX4.[98]
Targeting oncogenic signaling pathways in TNBC, such as the PI3K-AKT, MAPK, and androgen receptor (AR) pathways, has been approved for breast cancer treatment and is under clinical development.[99] The Hippo-YAP, AMP-activated protein kinase (AMPK), HIF1α, and mechanistic target of rapamycin complex 1 (mTORC1) signaling pathways regulate ferroptosis through various mechanisms.[86,100] It is noteworthy that different organelles, such as the mitochondria and the endoplasmic reticulum, regulate ferroptosis in an organelle-dependent manner. For example, ROS produced by mitochondrial metabolism can drive lipid peroxidation. Additionally, mitochondria can modulate iron ion metabolism and CoQ10 synthesis, thereby interfering with ferroptosis.[101] Over-activation of AKT maintains TRPML1/ARL8B-mediated lysosomal exocytosis, which reduces ferrous iron overload and membrane damage, and is involved in ferroptotic resistance.[102] Given the high levels of iron and lipid metabolism in TNBC tumors, the induction of ferroptosis is a promising therapeutic strategy worth exploring.[103] The crosstalk between oncogenic pathways and ferroptosis and its therapeutic potential are worth investigating.
Ferroptosis inducers in breast cancer
The mechanisms by which certain clinically used medicines to trogger ferroptosis in tumor cells have been extensively studied. This is relevant to multiple ferroptotic proteins, such as SLC7A11 (fenbendazole, propofol), GPX4 (propofol, flubendazole), transferrin receptor (TfR) (falnidamol), ferritin heavy/light chain (FTHL1/ FTL) (artesunate), and ACSL4 (propofol). Furthermore, ferroptosis has been thought to be a promising strategy in overcoming chemotherapy resistance.[104] Additionally, natural bioactive compounds also modulate NCOA4 (e.g., dihydroartemisinin and ursolic acid), influencing ferroptosis.[104]
Inhibiting the HSPA5/GPX4 pathway can enhance the sensitivity to gemcitabine in pancreatic cancer.[105] Likewise, pharmacological inhibition of SLC7A11 induces ferroptosis in pancreatic cancer cells, thereby enhancing the cytotoxic effects of gemcitabine and cisplatin.[106] Sorafenib, a tyrosine kinase inhibitor commonly used to treat advanced renal cell carcinoma, hepatocellular carcinoma, and thyroid cancer, causes ferroptosis in a range of cancer cells by suppressing SLC7A11.[104] At the same time, sorafenib also leads to GSH depletion and accumulation of lipid ROS.[107] Specifically, the p62-Keap1-NRF2 pathway regulates iron metabolism and lipid peroxidation by transcriptionally activating the expression of NQO1, HO1, and FTH1, conferring cancer cells ferroptosis resistance. Inhibiting the p62-Keap1-NRF2 pathway significantly enhances the anti-liver cancer activity of erastin and sorafenib, both in vitro and in vivo.[108] Recent studies have found that the chemotherapeutic drug imetelstat, used for treating acute myeloid leukemia, triggers ferroptosis through FADS2 and ACSL4-dependent lipid peroxidation metabolism.[109]
There is an emerging trend that a variety of small-molecule drugs and natural products function as potential ferroptotic inducers, offering novel therapeutic avenues for breast cancer (Figure 4). The underlying molecular mechanisms predominantly rely on the suppression of SLC7A11/ GPX4 signaling pathway, which drives the accumulation of lipid peroxides and enhances intracellular iron ion concentrations by interfering with iron metabolism (Figure 5). Several specific cases of breast cancer are as follows. An intriguing study revealed that erastin induces ferroptosis in MDA-MB-231 cells via the GSH/PDI/NO/ROS axis, leading to the production of lipid peroxidation in a manner independent of GPX4.[110] In breast cancer MCF-7 cells, quercetin promotes the degradation of the iron storage protein ferritin through the autophagic TFEB/LAMP-1 axis, resulting in elevated intracellular iron ion levels and subsequent ferroptosis.[111] A similar mechanism has been observed with phenazine derivatives in breast cancer cells, involving the upregulation of iron storage and transport proteins, such as IRP2, TfR1, and ferritin, resulting in iron overload.[112] In addition, dihydroisotanshinone I induces ferroptosis in MCF-7 and MDA-MB-231 cells by downregulating GPX4.[113] The pro-ferroptotic property of tanshinone IIA depends on its bioactivity in inhibiting the KDM1A/PIAS4/SLC7A11 axis; suppressed PIAS4 deactivates the SUMOylation of SLC7A11, in turn leading to SLC7A11 inactivation.[114] However, the research doesn’t provide any evidence for the alteration of the above histone modification mediated by the histone lysine demethylase LSD1/KDM1A. The bufalin targeting 2,4-dienoyl-CoA reductase (DECR1) relieves the coordination between DECR1 and SLC7A11/GPX4 axis.[115]
The molecular mechanisms of ferroptosis inducers against breast cancer. The orange means ferroptosis-inhibitory factor/proteins, while the blue represents ferroptosis-driving proteins. GSH refers to glutathione; GSSG denotes oxidized glutathione; Fe signifies iron ions; NO indicatesnitric oxide; ONOO-represents peroxynitrite; and PUFA stands for polyunsaturated fatty acids.
The molecular structures of representative ferroptosis inducers in breast cancer. Pink represents the ferroptosis-inducing compound: Erastin; blue indicates clinically approved drugs; light green denotes natural products: flavonoids; orange highlights natural products: acid or ester; brown exhibits saponins derived from plants; gray signifies unclassified natural products.
Tetrandrine citrate promotes ferroptosis by inhibiting GPX4 and activating NCOA4-mediated ferritin phagocytosis in breast cancer cells.[116] Red ginseng polysaccharide induces ferroptosis in lung cancer A549 and breast cancer MDA-MB-231 cells by downregulating GPX4,[117] whereas lycium barbarum polysaccharide induces ferroptosis in MDA-MB-231 and MCF-7 cells through the downregulation of SLC7A11 and GPX4.[118] Formosanin C, a saponin, has been identified as an effective ferroptosis inducer, characterized by the accumulation of lipid ROS and deprivation of GPX4 in MDA-MB-231 cells.[119] The pro-ferroptotic activity of salidroside and CT-1 (a derivative of cryptotanshinone; targeting and reducing FTH1) depends on NCOA4/FTH1-mediated ferritinophagy.[120,121] The terpenoids oridonin orchestrates RSL3 to induce ferroptosis in breast cancer cells via repressing the JNK/Nrf2/HO-1 pathway.[122] Similarly, peiminine induces ferroptosis through suppressing the Nrf2/HO-1/NQO1 axis,[123] while ursolic acid inhibits Keap1/Nrf2 axis to induce ferroptosis in breast cancer.[124] The pro-ferroptosis effect of Paris saponin VII and myricetin involves downregulation of the Nrf2/GPX4 axis.[125,126] The triterpenoid saponin, Platycodin D2, induces ferroptosis mediated by mitochondrial ROS and autophagic inhibition.[127]
The clinical anesthetic drug propofol (propofol) induces ferroptosis in MDA-MB-231 cells by modulating the P53/SLC7A11/GPX4 pathway.[128] Another anesthetic, ketamine, induces ferroptosis in breast cancer MCF-7 and T47D cells by inhibiting the KAT5/GPX4 axis.[129] The local anesthetic lidocaine facilitates ferroptosis in breast cancer T47D cells through the miR-382-5p/SLC7A11 axis.[130] Moreover, antidiabetic drug metformin induces ferroptosis by inhibiting lncRNA H19-mediated autophagy.[131] Another study has reported that metformin-induced ferroptosis in breast cancer cells is associated with the downregulation of SLC7A11 through ubiquitin-like modification (UFMylation).[132] Metformin also promotes ferroptosis in MDA-MB-231 cells by targeting the miR-324-3p/GPX4 axis.[133] Additionally, chemotherapeutic agent doxorubicin (DOX, or adriamycin) leads to ferroptosis in breast cancer cells, whereas DNAJC12 attenuates above effect via activating PI3K-AKT pathway to facilitate DOX-involved chemoresistance;[134] DOX also activates nicotinamide adenine dinucleotide phosphate oxidase (NOX) to promote hydrogen peroxide (H2O2)/Fenton reaction in breast cancer cells;[135] the effect of ferroptosis induction of Notoginsenoside R1 also depends on the activation of NOX1.[136] Pharmacological activation of GPX4, however, alleviates DOX-induced heart damage and cardiotoxicity.[137] In TNBC cells, the statins drug (simvastatin) weakens the HMGCR/MVA/GPX4 axis to initiate ferroptosis,[138] while pitavastatin induces autophagy-dependent ferroptosis.[139] The phase II clinical trial to estimate the effectiveness of simvastatin with NAC is currently underway (NCT05550415).[140] Simeprevir, the agent against hepatitis C infection, induces ferroptosis via modulating the β-TrCP/Nrf2/GPX4 axis.[141] Niclosamide, an antiparasitic medicine, decreases the expression of glutamine transporters SLC38A5 and SLC7A11 to induce ferroptosis in TNBC cells.[142] Ononin, a flavonoid, induces ferroptosis via suppressing the Nrf2/SLC7A11 axis.[143] The flavone oxyresveratrol leads to ferroptosis through inhibiting the EGFR/PI3K/AKT/GPX4 pathway axis in breast cancer.[144]
Curcumin increases the expression of the glutamine transporter SLC1A5 in MDA-MB-453 and MCF-7 cells to regulate the SLC1A5/GLS2/GOT1 pathway, leading to elevated lipid peroxides and subsequent ferroptosis.[145] In contrast, in lung cancer cells, curcumin induces ferroptosis by upregulating ACSL4 and downregulating the SLC7A11/GPX4 axis.[146] Besides, vulpinic acid, a metabolite of lichen, induces lipid peroxidation-driven ferroptosis through upregulating LPCAT3 in luminal A breast cancer cells.[147] Conjugated linoleic acid triggers ferroptosis in breast cancer through ACSL1-mediated lipid peroxidation, independent of GPX4.[148] Glycyrrhetinic acid induces ROS/RNS-mediated ferroptosis in breast cancer MDA-MB-231 cells by activating NADPH oxidase and iNOS while depleting GSH levels.[149] Phenylethyl caffeate (CAPE) activates AMPK to induce ferroptosis in TNBC cells.[150,151] In addition, polyphyllin III induces ferroptosis in MDA-MB-231 cells by upregulating ACSL4, resulting in lipid peroxide accumulation.[152] Eupaformosanin promotes the ubiquitin-mediated degradation of mutant P53, leading to the accumulation of lipid reactive oxygen species and iron ions, ultimately triggering ferroptosis in triple-negative breast cancer cells.[153] Formononetin, an isoflavone and FGFR2 inhibitor, induces ferroptosis via regulating the mTORC1/SREBP1/SCD1 axis.[154]
Crosstalk between ferroptosis and tumor immune microenvironment
Immunotherapy, a novel and emerging strategy against solid cancers, has rapidly advanced in recent years, demonstrating significant effectiveness and potential for curing various carcinomas, even refractory tumors.[155] Immune checkpoint inhibitors (ICIs) have been successfully implemented in cancer therapy through blocking immunosuppressive receptors, such as cytotoxic T lymphocyte antigen-4 (CTLA-4) and PD-1 in T cells, thereby enhancing the cytotoxicity and proliferative capacity of tumor-infiltrating lymphocytes (TILs). Classic ICIs include monoclonal antibodies targeting programmed cell death protein 1 (PD-1; pembrolizumab, nivolumab), programmed death ligand 1 (PD-L1, atezolizumab, durvalumab, avelumab), and CTLA-4 (ipilimumab).[156] In 2019, the US Food and Drug Administration (FDA) approved the first ICI treatment regimen for breast cancer (pembrolizumab). The anti-PD-L1 antibody atezolizumab, in combination with nab-paclitaxel, was approved as a first-line treatment for PD-L1-positive metastatic TNBC patients.[157,158] ICIs have demonstrated survival benefits in both advanced and early-stage TNBC patients.[159] The genomic instability and mutational burden characteristic of TNBC patients lead to the generation of a greater number of neoantigens, which are recognized by the adaptive immune system, thereby stimulating an antitumor immune response. Consequently, TNBC exhibits higher levels of TILs and elevated expression of PD-L1, compared to other breast cancer subtypes. The ligand PD-L1 and its receptor PD-1 are involved in the regulation of immune tolerance. The levels of neoantigens and PD-L1 expression serve as foundational criteria for administering immunotherapy to TNBC patients.[14,160] The expression status of PD-L1, the abundance of TILs, and the tumor mutational burden (TMB) are three pivotal factors influencing the response to ICI. In the context of anti-PD-1/PD-L1 therapy, PD-L1-positive TNBC patients generally exhibit improved efficacy compared to their PD-L1-negative counterparts. Conversely, patients with other subtypes of breast cancer generally exhibit lower PD-L1 expression and reduced TIL infiltration, indicating a diminished response to immunotherapeutic interventions.[161] Moreover, in PD-L1-positive TNBC patients, the anti-PD-1 antibody pembrolizumab combined with chemotherapy has demonstrated improved patient survival compared to chemotherapy alone.[162] In addition to its usage in combination with chemotherapy, clinical trials are underway to assess the efficacy of ICIs in conjunction with other treatments, including anti-angiogenic agents, PPAR inhibitors, and various immunotherapeutic approaches (cancer vaccines and immunomodulators).[99] Notably, the efficacy of ICIs in different subtypes of TNBC remains uncertain. STAT inhibitors, cytokines or cytokine receptor antibodies, and ipilimumab (a CTLA-4 inhibitor) may be utilized for the treatment of BLIA subtype.[17] In the LAR subtype of TNBC, characterized by upregulation of phosphatidylethanolamine and glutathione metabolism (particularly involving GPX4), the induction of ferroptosis through GPX4 inhibitors may enhance the efficacy of anti-PD-1 combinations.[163]
The small molecule compound liproxtatin-1, which inhibits lipid peroxidation of ferroptosis, significantly reduces the antitumor effects of immune checkpoint inhibitors. These findings suggest a connection and interplay between immune checkpoint blockade and ferroptosis.[164] There are two approaches described in the literature to reverse therapy resistance and enhance the effectiveness of immunotherapy through the induction of ferroptosis. The first is an intrinsic method, involving the induction of ferroptosis within cancer cells to trigger a vaccine-like effect that stimulates antitumor immunity. The second is an extrinsic method, which entails to trigger ferroptosis in the tumor microenvironment to deplete immunosuppressive cells.[165,166] For instance, cancer cells that undergo ferroptosis can release damage-associated molecular pattern components (DAMPs) that promote the maturation of bone marrow-derived dendritic cells.[167] Additionally, ferroptotic cancer cells express specific phospholipid components that bind to toll-like receptor 2 (TLR2) on the surface of macrophages, enhancing their phagocytic activity.[168] Furthermore, TGFβ1 released by macrophages promotes ferroptosis through transcriptional repression of SLC7A11 in the TGFBR/SMAD signaling pathway.[169] Knockout of SLC7A11 in macrophages inhibits tumor progression and metastasis in murine liver cancer models by reducing the recruitment and infiltration of tumor-associated macrophages (TAMs), suppressing M2 polarization and enhancing the ferroptosis sensitivity of TAMs. Conversely, TNBC cell-secreted FOXM1 transactivates IDO1 to inhibit ferroptosis and promote M2 polarization of TAMs.[170] Targeting SLC7A11 in TAMs using nanotechnology has been observed to enhance the antitumor efficacy of anti-PD-L1 therapies.[171] Beyond immune checkpoints, co-stimulatory or co-inhibitory signals in T cells and antigen-presenting cells are also involved in the mechanisms of ferroptosis, and impact antitumor immunity;[86] however, this aspect is not the primary focus of this review. The simultaneous targeting of ferroptosis and the tumor microenvironment through drug delivery/nanomedicine or biomaterials is feasible, but it is not included in our scope.[172, 173, 174, 175] Here, we aim to explore the feasibility of directly modulating both PD-L1 and tumor cell ferroptosis through small molecules or key proteins (e.g., transcription factors and epigenetic modulators), particularly in the context of breast cancer. This approach may benefit tumor immunotherapy based on immune checkpoint inhibition, reduce the adverse effects associated with combination therapies, and even provide new alternatives for cancer pharmacotherapy.
Ferroptosis inducers directly modulate PD-L1 expression
Fascaplysin, a natural product isolated from sponges, induces ferroptosis in lung cancer cells by promoting ROS accumulation and downregulating GPX4. Meanwhile, it upregulates PD-L1 expression, enhancing the efficacy of anti-PD-1 immunotherapy in mouse models.[176] Eicosapentaenoic acid triggers ferroptosis by inhibiting the Nrf2/GPX4 pathway while concurrently suppressing IL-6/STAT3 signaling to reduce PD-L1 expression, thereby increasing sensitivity of osteosarcoma to cisplatin.[177,178] Ferroptosis inducers (such as erastin and RSL3) have been reported to upregulate PD-L1 expression in TNBC cells, which may benefit immunotherapy in high-risk early TNBC patients following neoadjuvant chemotherapy.[179] Additionally, in recurrent TNBC, ferroptosis inducers may exhibit potential synergistic effects with anti-PD-L1 immunotherapy.[179]
The upstream transcriptional factors of PD-L1 have been extensively investigated in immune evasion and clinical pharmacotherapy, such as Nrf2, STAT3.[180,181] On the other hand, they have great potential for ferroptosis regulation. For instance, Nrf2 transactivates anti-ferroptotic factors involving iron metabolism (e.g., FTH1) and GSH metabolism (e.g., SLC7A11, GPX4, and PRDX1) to prevent cancer cells from ferroptosis.[182] Additionally, STAT3 transcriptionally upregulates the SLC7A11/GPX4 axis and FTH1 to resist ferroptosis;[183,184] STAT3 has been reported to modulate TAM recruitment and activation in a ferroptosis-dependent manner, dominating immunotherapy efficiency.[185] These results suggest that targeting the common upstream ferroptosis drivers and immunosuppressive factors to induce cancer cell ferroptosis and reshape TME is promising and forthcoming. Natural products may kill two birds with one stone by targeting these transcription factors in anticancer therapy.
Bridging ferroptosis and antitumor immunity
The CD8+ T cells derived interferon gamma (IFN-γ) inhibits the transcription of SLC7A11 and SLC3A2, which together form the cystine/ glutamate antiporter system xc-, through the activation of signal transducer and activator of transcription 1 (STAT1). This mechanism subsequently triggers ferroptosis in cancer cells.[164] Similarly, radiotherapy activates ataxia telangiectasia mutated protein (ATM) to suppress the expression of SLC7A11, thereby enhancing ferroptosis sensitivity.[186] Another case is that IFN-γ activates interferon receptor (IFNR)/JAK/STAT1 signaling pathway, causing the transcriptional factor interferon regulatory factor 1(IRF1) to transactivate ACSL4 expression in tumor cells. This subsequently alters the ACSL4-mediated neoplastic lipidomic.[187] Notedly, the NOD-, LRR- and CARD-containing 5 (NLRC5) is activated by IFN-γ/STAT1 axis; NLRC5, the key upstream transcriptional factor of the major histocompatibility complex class I (MHC-I) family, facilitates neoantigen presentation in tumor immunity.[188] Recently, ACSL promotes MHC-I-mediated antigen presentation (membrane protein involving the recognition of T cells towards tumor cells) in a NLRC5-dependent manner, enhancing anti-PD1 immunotherapy efficiency.[189] These results imply that there is a potential crosstalk between ferroptotic driver ACSL4 and tumor microenvironment.
Protein kinase C (PKC), a family of protein kinases, includes eight PKC isozymes (i.e., PKCα, PKCβΙ, PKCβΙΙ, PKCγ, PKCδ, PKCɛ, PKCθ, and PKCη), which regulate the activity of downstream proteins by phosphorylating their serine/threonine residues.[190] PKCβII, activated by ferroptosis inducer-driven lipid peroxide, phosphorylates ACSL4 at Thr328 to activate ACSL4, which triggers biosynthesis of PUFA-containing lipids. Finally, the lipid peroxidation-PKCβII-ACSL4 positive feedback axis initiates ferroptosis by promoting lipid peroxidation to amplify it to lethal levels. Targeting the PKCβII-ACSL4 axis augments the efficacy of ICI therapy.[191] The further clinical study finds that ACSL4 expression is highly associated with T cell-related immune score and is a potential predictor for anti-PD1 immunotherapy response.[191] Among melanoma patients, those with high ACSL4 expression have better sensitivity towards immunotherapy.[187] Simultaneously, ACSL4 is regarded as an immune-related prognostic biomarker in cholangiocarcinoma.[192] However, how ACSL4 influences T cell-involving antitumoral effects and underlying cell communications needs further investigation.
Androgen Receptor (AR) is expressed in over 70% of breast cancer, and its transactivation facilitates breast cancer progression in a subtype-dependent manner; targeting AR is considered an alternative strategy for treating breast cancer due to the success of AR inhibitors in prostate cancer.[193] Transnationally upregulated by AR, membrane-bound O-acyltransferase domain-containing 1 and 2 (MBOAT1/2), remodels cellular phospholipid composition to inhibit ferroptosis in breast cancer through a mechanism independent of GPX4 or FSP1.[194] Naturally, higher levels of AR expression and activity were observed in male breast cancer compared with female breast cancer.[195] Approximately 20%–40% of TNBC patients are of the LAR subtype, which is characterized by luminal-like gene expression, neoadjuvant chemotherapy resistance, and AR overexpression; AR directly transactivates GPX4 in LAR TNBC.[163] A series of clinical trials focuses on the treatment potential of targeted AR in AR-positive breast cancer patients,[196] including in combination with anti-PD-1 drugs.[197] Whether AR affects, however, PD-L1 expression or even immune checkpoint blockade efficacy is inconclusive.
It is well-known that cancer epigenomics reshapes anti-tumor immunity, and epigenomic therapy has been employed in breast cancer.[198, 199, 200] BRD4, the “reader” of histone acetylation, facilitates permissive gene transcription;[201,202] BRD4 inhibitor is a potential ferroptosis inducer in breast cancer via deactivating ferroptotic defense system[203, 204, 205] and inducing ferritinophagy.[61] Meanwhile, ACSS2, an acetyl-CoA synthetase, confers cellular proteins acetylation, including histone proteins; it also inhibits ferroptosis via the E2F1/SLC7A11/GPX4 axis in breast cancer brain metastatic cells.[206] Additionally, the enhancer of Zeste 2 (EZH2), a subunit of polycomb repressive complex 2 (PRC2) that methylates histone H3 lysine 27 trimethylation (H3K27me3) to induce gene silencing, while AR is transactivated by EZH2 without a classic transcription-inhibitory role.[207,208] EZH2 downregulates PD-L1 expression and stability in hepatocellular and colorectal cancer, respectively.[209,210] Conversely, EZH2 positively modulates PD-L1 expression in non-small cell lung cancer.[211] On the other hand, EZH2 suppresses ferroptosis in hepatocellular cancer (downregulating transferrin receptors-2: TFR2, upregulating FSP1 and SLC7A11)[212,213] and esophageal squamous carcinoma (inhibiting ACSL4).[214] These evidences suggest EZHZ inhibition (EZH2 inhibitor, tazemetostat) is a potent strategy to realize co-targeting ferroptosis and suppressive TME (e.g., PD-L1-mediated immune evasion) in breast cancer.
Another promising epigenetic modulator concurrently realizes that it is protein arginine methyltransferase family (PRMT), the writers of arginine methylation consisting of nine members: PRMT1-3, CARM1(PRMT4), PRMT5-9 that induces ferroptosis and inhibits suppressive TME.[215] It methylates arginine to deeply involve protein post-translational modification and histone modification-mediated gene transcription in cancers.[216] Numerous studies have unveiled that PRMT1 and PRMT5 function as tumor drivers in breast cancer through methylating key proteins of onco-pathways and promoting oncogene transcription (PRMT1 confers asymmetric di-methylation of arginine (R) 3 residue of histone H4:H4R3me2a; PRMT5 catalyzes symmetric di-methylation of histone H3 arginine 2:H3R2me2s).[217] PRMT1 and PRMT5 inhibitors have been introduced into phase I clinical trials for various solid tumors and hematoma.[215,216] Excitingly, PRMT5 methylates GPX4 and maintains GPX4 stabilization by preventing FBW7-mediated GPX4 ubiquitination, highlighting that PRMT5 inhibition may improve ferroptotic sensitivity.[218] However, a recent work exhibites PRMT1, serving as a pro-ferroptotic driver, decreases SLC7A11 transcription and inhibits FSP1 activity through methylating FSP1, which enhances ferroptosis sensitivity in acute liver injury.[219] Whether PRMT can intervene ferroptosis by regulating the transcriptional expression of key ferroptotic factors in a histone modification-dependent manner remains understudied. Licochalcones have extensive anti-tumor bioactivity, involving regulation of multiple oncogenic pathways (e.g., EGFR/ERK, PI3K/AKT/mTOR, p38/JNK, JAK2/STAT3) and perturbation of cancerous phenotypes (proliferation, apoptosis, autophagy, and so on).[220] Licochalcone A induces ferroptosis in liver cancer cells through downregulating the SLC7A11/GPX4 axis;[221] it is also identified as a PRMT6 inhibitor for breast cancer treatment in preclinical research.[222] However, the potential property of licochalcones to induce ferroptosis and reshape TME in a PRMT-dependent manner is poorly understood.
In brief, we expect more research that focuses on the feasibility of co-targeting ferroptosis and TME through regulating transcriptional factors or epigenomic modulators in breast cancer from bench to bedside. It is promising and reasonable to dig hit and lead compounds from natural products to achieve the above concept (Figure 6).
![Figure 6 The crosstalk between ferroptosis and tumor immunity. Elaidic acid-activated ACSL5 promotes the NLRC5/MHC-I axis to enhance antigen presentation.[189] TGFβ1 released by macrophages promote tumoral ferroptosis through activating transcriptional factor SMAD to inhibit SLC7A11 expression.[169] CD4+ T cell-released IL1β facilitates neutrophil ferroptosis; these ferroptotic neutrophils dysfunction CD8+ T cells through generating immune-inhibiting factors.[223] ACSL3 attenuates T-cell efficacy through promoting PAI-1 release.[224] CD8+ T cell-driven IFN-γ promotes tumor ferroptosis through enhancing IFNR/IRF1/ACSL4[187] and inhibits SLC7A11 and SLC3A2 transcription through IFNGR/JAK/STAT1.[164] AA: arachidonic acid; PAI-1: plasminogen activator inhibitor type.](/document/doi/10.1515/jtim-2025-0093/asset/graphic/j_jtim-2025-0093_fig_006.jpg)
The crosstalk between ferroptosis and tumor immunity. Elaidic acid-activated ACSL5 promotes the NLRC5/MHC-I axis to enhance antigen presentation.[189] TGFβ1 released by macrophages promote tumoral ferroptosis through activating transcriptional factor SMAD to inhibit SLC7A11 expression.[169] CD4+ T cell-released IL1β facilitates neutrophil ferroptosis; these ferroptotic neutrophils dysfunction CD8+ T cells through generating immune-inhibiting factors.[223] ACSL3 attenuates T-cell efficacy through promoting PAI-1 release.[224] CD8+ T cell-driven IFN-γ promotes tumor ferroptosis through enhancing IFNR/IRF1/ACSL4[187] and inhibits SLC7A11 and SLC3A2 transcription through IFNGR/JAK/STAT1.[164] AA: arachidonic acid; PAI-1: plasminogen activator inhibitor type.
Conclusion
Based on the core regulatory signals of ferroptosis, the signal regulation of ferroptosis in breast cancer mainly focuses on transcriptional regulation and degradation of ferroptosis-regulated proteins. For instance, transcription factors (Nrf2, p53, SP1) directly transactivates SLC7A11 and GPX4. BRCA1 and CST1 promote and inhibit the ubiquitination degradation of GPX4, respectively. Furthermore, natural products considered as the molecular library have great potential for further screening of potential ferroptosis inducers to combat carcinomas, including breast cancer.[22,225] Given the diversity of natural product structures, flavonoids and terpene constituents (e.g., glycyrrhetinic acid and platycodin D2) may have better potential as ferroptosis inducers. Mechanistically, these molecules trigger tumor ferroptosis through three ferroptotic regulatory mechanisms: the antioxidant system, iron metabolism, and lipid metabolism. However, most pharmacological studies have focused only on antioxidant system (mainly on the Nrf2/GPX4 axis) and lacked insights towards how small molecules target proteins target to modulate ferroptotic signaling pathways. Importantly, ferroptosis is also considered a form of immunogenic cell death, as evidenced by the release of immune regulatory molecules known as damage-associated molecular patterns (DAMPs), such as oxidized high mobility group box 1 (HMGB1), decorin, and TLR2.[226,227] Additionally, immune cell-derived cytokines such as IFN-γ modulate the ferroptosis signaling in tumor cells, thereby affecting their sensitivity to ferroptosis. These findings underscore the interplay between ferroptosis in tumor and immune cells within TME. Targeting transcription factors (e.g., STAT3, AR, and Nrf2) or epigenetic regulators (e.g., EZH2 and PRMT) could facilitate a strategy that induces ferroptosis while simultaneously inhibiting tumor-promoting immunity. Natural products and small molecule drugs may achieve the functions of co-regulating ferroptosis and TME.
Ferroptosis-regulating proteins may not simply promote or inhibit the initiation and occurrence of ferroptosis, but rather depend on the specific molecular context. For instance, activating transcription factor 4 (ATF4) is a transcription factor that activates HSPA5, which binds to GPX4 to prevent its degradation and subsequently helps cancer cells resist ferroptosis.[105] Under endoplasmic reticulum stress, ATF4 directly and transcriptionally activates ferroptosis-related proteins, such as SLC7A11, HSPA5, and CHOP, to either promote or inhibit ferroptosis.[39] Whether ATF4 and other members of the ATF family simultaneously regulate ferroptosis and immune checkpoints at the transcriptional level warrants further investigation. Similarly, ferroptosis occurring in anti-tumor immune cells and immunosuppressive cells is a “double-edged sword”.[86] A recent study on chemoresistant TME in breast cancer showed that neutrophil ferroptosis is mediated by the IL1β/IL1R1/NF-κb/MBOAT1 signaling, and immunosuppressive factors (PGE2, IDO, and oxidized lipids) released by these dead neutrophils alleviate the antitumor effect of CD8+ T-cells.[223] Conversely, CT1, a derivative of cryptotanshinone, induces ferroptosis in TNBC cells and recruits pro-tumor N2-type neutrophils to combat breast cancer.[121] Therefore, when applying ferroptosis induction strategies, it is necessary to consider distinct ferroptosis sensitivity and response mechanisms among tumor cells, anti-tumor immune cells, and immunosuppressive cells, to prevent damage to positive immune cells.
This review has some limitations. The ferroptotic molecular mechanisms and clinical implications of non-coding RNAs in breast cancer are beyond our scope.[228,229] Given the complex composition of extracts of medicinal plants or ethnopharmacology, we did not address them in this review.[230] However, the potential contributions of Chinese herbal extracts to ferroptosis have been summarized.[231] Moreover, one review has regarded ferroptosis as a therapeutic strategy for TNBC (overcoming drug resistance and combination therapy).[140,232,234] Another review described the molecular mechanisms of ferroptosis in breast cancer.[235] Our review provides a more comprehensive view of how natural products induce ferroptosis to combat breast cancer, compared with the previous literature.[236] We underscore representative ferroptotic modulators and pathways in breast cancer, and natural products/ ferroptosis inducers against breast cancer. There are some difficulties in co-targeting ferroptosis and immune evasion:
(1) target availability, how to find novel targets mediating ferroptosis to initiate and modulate the expression of tumor immune molecules requires further practice (e.g., CRISPER screening, single-cell sequencing), based on the interplay of “ferroptosis-immunity” (ferroptosis-immune crosstalk). However, targeting transcription factors or epigenetic regulators is potential and promising (e.g., STAT3, Nrf2, AR, EZH2, PRMT); (2) drug efficiency, improvement the targeting and immune regulatory effects of small molecule drugs cannot be achieved simultaneously. The reshaping effect of small molecule drugs on TME cannot be ignored (differences in ferroptotic sensitivity between tumor cells and immune cells). Screening new lead compounds from natural products or FDA-approved drug library and studying structure-activity relationships may provide alternative therapeutic strategies (Figure 7).
The potential challenges and resolutions of targeting the crosstalk between ferroptosis and tumor microenvironment.
The effectiveness of ferroptosis targeting has been preliminarily confirmed in a series of clinical trials (Table 1).[237,238] As expected, GPX4/SLC7A11 inhibitor and ACSL4 agonist have attracted considerable interest from researchers; however, strategies targeting iron metabolism are lacking. Additionally, despite advances in immunotherapy based on immune checkpoint blockade in breast cancer, the combination of immunotherapy with other strategies (such as ferroptosis induction) is being explored to improve efficacy and maximize patient benefits.[14] As forementioned, several clinical drugs have shown potential to induce ferroptosis,[104] which has also been reported as an alternative strategy for reversing first-line anti-tumor drug resistance (olaparib, cetuximab, and gefitinib).[165] Although ferroptosis plays a crucial role in immunotherapy, little is known about its role in breast cancer, particularly TNBC.[239] Future research should focus on the epigenetic (e.g., histone modifications) and post-transcriptional regulations (e.g., protein acetylation) of ferroptosis regulators in breast cancer. Additionally, exploring the potential role of ferroptosis in the immune microenvironment could enhance therapeutic efficacy, including, but not limited to, immunotherapy. Ferroptosis inducers may represent a promising alternative strategy for breast cancer treatment. Collectively, natural products are potential ferroptosis inducers and diverse molecular scaffolds for further drug design and development. This review also lays a theoretical foundation for co-targeting the crosstalk between ferroptosis and tumor microenvironment.
The clinical trials for ferroptosis-inducing strategies in cancers.
| Targeted pathway | Target | Drug | Phase | Cancer | ID |
|---|---|---|---|---|---|
| Anti-oxidation metabolism | GSH | Cisplatin | III | NSCLC | NCT01656551 |
| DHODH | Brequinar | I, II | AML | NCT03760666 | |
| GCL | Buthionine | I | Neuroblastoma | NCT00002730 | |
| GCL | Sulfoximine | I | Neuroblastoma | NCT00005835 | |
| GPX4 | Altretamine | I | Lymphoma, arcoma | NCT00002936 | |
| GPX4 | Withaferin A | II | Osteosarcoma | NCT00689195 | |
| SLC7A11 | Sorafenib | II, III | HCC | NCT03794440 | |
| SLC7A11 | Sorafenib | I, II | AML | NCT03247088 | |
| SLC7A11 | Sorafenib | II | Neuroblastoma | NCT02559778 | |
| SLC7A11 | Sorafenib | II | NSCLC | NCT00064350 | |
| SLC7A11 | Sulfasalazine | N/A | Glioma | NCT01577966 | |
| SLC7A11 | Sulfasalazine | I | Glioblastoma | NCT04205357 | |
| SLC7A11 | Sulfasalazine | II | Breast cancer | NCT03847311 | |
| SLC7A11 | Temozolomide | III | Glioma | NCT00626990 | |
| HMGCR | Fluvastatin | II | Breast cancer | NCT00416403 | |
| HMGCR | Simvastatin | II | Breast cancer | NCT00354640 | |
| TXNRD | Auranofin | I, II | Glioblastoma | NCT02770378 | |
| TXNRD | Auranofin | I, II | NSCLC | NCT01737502 | |
| TXNRD | Auranofin | II | CML | NCT01419691 | |
| TXNRD | Auranofin | I | RPF | NCT01747798 | |
| Iron metabolism | FT | Artesunate | I | Breast cancer | NCT00764036 |
| Iron chelator | Ciclopirox Olamine | I | Hematologic malignancy | NCT00990587 | |
| Lipid metabolism | DRD2 | Haloperidol | II | Glioblastoma | NCT06218524 |
| LOX | NDGA | II | Prostate cancer | NCT00678015 | |
| ACSL4 | Pioglitazone | II | Breast cancer | NCT05013255 | |
| ACSL4 | Rosiglitazone | III | Prostate cancer | NCT00182052 | |
| ACSL4 | Rosiglitazone | II | Solid tumors | NCT04114136 | |
| ACSL4 | Rosiglitazone | II | Sarcoma | NCT00004180 | |
| ACSL4 | Troglitazone | II | Sarcoma | NCT00003058 | |
| ALOX5 | Zileuton | I | CML | NCT02047149 | |
| ALOX5 | Zileuton | I | CML | NCT01130688 | |
| ALOX5 | Zileuton | II | Head and neck cancer | NCT00056004 | |
| ALOX5 | Zileuton | II | Lung cancer | NCT00070486 |
AML: acute myeloid leukemia; CML: chronic myelogenous leukemia; DHODH: dihydroorotate dehydrogenase; DRD2: dopamine D2 receptor; FT: ferritin; GCL: glutamate cysteine ligase; HCC: hepatocellular carcinoma; HMGCR: 3- hydroxy-3-methylglutaryl-CoA reductase; LOX: lipoxygenase; N/A: not applicable; NDGA: nordihydroguaiaretic acid; NSCLC: non-small cell lung cancer; RPF: recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer; TXNRD: thioredoxin reductase. Data from ClinicalTrals.gov.
Funding statement: The study was supported by National Natural Science Foundation of Science and Technology Department of Sichuan Province (no.2023NSFSC1928), Project of State Administration of Traditional Chinese Medicine of China (no. ZYYCXTD-D-202209), and Project of Sichuan Provincial Administration of Traditional Chinese Medicine (no.2022C001), the Open Research Fund of State Key Laboratory of Southwestern Chinese Medicine Resources (no. SKLTCM202404), Sichuan University Interdisciplinary Innovation Fund.
Acknowledgements
Figure 7 was created with bioRender. We sincerely appreciate all editors and reviewers.
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Authors’ Contributions
J. Zhou: Conceptualization, Software, Writing - Original Draft; W. Yang: Writing - Original Draft; H. Tang and Y. Zou: Data Curation, Writing - Review & Editing. Z. Zhou and C. Peng: Funding acquisition, Writing - Review & Editing. F. Peng: Supervision, Funding acquisition, Writing - Review & Editing.
-
Ethical Approval
Not applicable.
-
Informed Consent
Not applicable.
-
Conflict of Interest
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.
-
Use of Large Language Models, AI and Machine Learning Tools
None declared.
-
Data Availability Statement
Not applicable.
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© 2025 Jianbo Zhou, Wangji Yang, Hailin Tang, Yutian Zou, Zhaokai Zhou, Cheng Peng, Fu Peng, published by De Gruyter on behalf of Scholar Media Publishing
This work is licensed under the Creative Commons Attribution 4.0 International License.
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