Ferroptosis in breast cancer: From adipocyte–immune–iron regulation to therapeutic application

Abstract

Background: Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a potential therapeutic vulnerability in breast cancer. However, increasing evidence indicates that ferroptosis sensitivity is not solely determined by tumour-intrinsic factors, but is dynamically regulated by the tumour microenvironment (TME), particularly through interactions among adipocytes, immune cells and iron metabolism.

Main body: Recent studies provide mechanistic evidence for this context dependence. Adipocyte-derived monounsaturated fatty acids such as oleic acid suppress lipid peroxidation and increase resistance to ferroptosis induction in triple-negative breast cancer, whereas ACSL4-driven polyunsaturated phospholipid remodelling enhances ferroptosis susceptibility. In parallel, CD8⁺ T-cell-derived interferon-γ promotes ferroptosis by suppressing SLC7A11-mediated cystine uptake, while tumour-associated macrophages buffer oxidative stress through iron sequestration and glutathione-dependent antioxidant programs. These opposing forces indicate that ferroptosis is governed by a coordinated adipocyte–immune–iron regulatory network rather than a single pathway. Unlike previous reviews focused mainly on tumour–intrinsic mechanisms or general TME effects, this review integrates adipocyte-derived lipid metabolism, immune-mediated redox regulation, iron handling and spatial heterogeneity into a unified ‘ferroptosis ecosystem’ framework. Based on this concept, we propose eco-ferrotherapy, a translational strategy aimed at simultaneously targeting tumour-intrinsic pathways and microenvironmental buffering systems. This framework may support subtype-specific therapeutic prioritisation, biomarker-guided patient stratification and rational combination strategies involving immunotherapy and nanomedicine.

Conclusion: Ferroptosis in breast cancer should be understood as an ecosystem-level vulnerability shaped by metabolic, immune and spatial factors. Defining and therapeutically targeting this ferroptosis ecosystem provides a conceptual and translational roadmap for improving precision treatment strategies.

Keywords

adipocytes / breast cancer / ferroptosis / immune cells / iron metabolism / precision medicine / tumour microenvironment

References

[1] Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death [J]. Cell. 2012; 149(5): 1060-1072.

[2] Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease [J]. Nat Rev Mol Cell Biol. 2021; 22(4): 266-282.

[3] Wu Y, Zhang S, Gong X, et al. The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression [J]. Mol Cancer. 2020; 19(1): 39.

[4] Xu S, Chaudhary O, Rodríguez-Morales P, et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8(+) T cells in tumors [J]. Immunity. 2021; 54(7): 1561-1577.e7.

[5] Zhang Z, Lu M, Chen C, et al. Holo-lactoferrin: the link between ferroptosis and radiotherapy in triple-negative breast cancer [J]. Theranostics. 2021; 11(7): 3167-3182.

[6] Nourollahian T, Taghavi S, Abnous K, et al. Targeted doxorubicin-loaded core-shell copper peroxide-mesoporous silica nanoparticles for combination of ferroptosis and chemotherapy of metastatic breast cancer [J]. Int J Pharm. 2024; 662:124487.

[7] Vande Voorde J, Ackermann T, Pfetzer N, et al. Improving the metabolic fidelity of cancer models with a physiological cell culture medium [J]. Sci Adv. 2019; 5(1):eaau7314.

[8] Doll S, Proneth B, Tyurina YY, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition [J]. Nat Chem Biol. 2017; 13(1): 91-98.

[9] Kagan VE, Mao G, Qu F, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis [J]. Nat Chem Biol. 2017; 13(1): 81-90.

[10] Xie Y, Wang B, Zhao Y, et al. Mammary adipocytes protect triple-negative breast cancer cells from ferroptosis [J]. J Hematol Oncol. 2022; 15(1): 72.

[11] Xiong H, Zhai Y, Meng Y, et al. Acidosis activates breast cancer ferroptosis through ZFAND5/SLC3A2 signaling axis and elicits M1 macrophage polarization [J]. Cancer Lett. 2024; 587:216732.

[12] Chen Z, Li R, Fang M, et al. Integrated analysis of FKBP1A/SLC3A2 axis in everolimus inducing ferroptosis of breast cancer and anti-proliferation of T lymphocyte [J]. Int J Med Sci. 2023; 20(8): 1060-1078.

[13] Yang F, Xiao Y, Ding JH, et al. Ferroptosis heterogeneity in triple-negative breast cancer reveals an innovative immunotherapy combination strategy [J]. Cell Metab. 2023; 35(1): 84-100.e8.

[14] Nagpal A, Needham K, Lane DJR, et al. Integrin αvβ3 Is a Master Regulator of Resistance to TKI-Induced Ferroptosis in HER2-Positive Breast Cancer [J]. Cancers. 2023; 15(4): 1216.

[15] Pottier C, Montero-Ruiz L, Jehay R, et al. Targeting ferroptosis resistance resensitizes metastatic HR(+)HER2(-) breast cancer cells to palbociclib-hormone therapy [J]. Cancer Communications (London, England). 2025; 45(4): 460-464.

[16] Zeng C, Wang J, Zhao S, et al. Multi-cohort validation of a lipid metabolism and ferroptosis-associated index for prognosis and immunotherapy response prediction in hormone receptor-positive breast cancer [J]. Int J Biol Sci. 2025; 21(9): 3968-3992.

[17] Wang Z, Li R, Hou N, et al. PRMT5 reduces immunotherapy efficacy in triple-negative breast cancer by methylating KEAP1 and inhibiting ferroptosis [J]. J Immunother Cancer. 2023; 11(6):e006890.

[18] Wang T, Zhang Y, Liu H, et al. FOXM1 derived from triple-negative breast cancer exosomes promotes cancer progression by activating IDO1 transcription in macrophages to suppress ferroptosis and induce M2 polarization of tumor-associated macrophages [J]. Genes Genet Syst. 2025; 100;24-00079.

[19] Ye S, Hu X, Sun S, et al. Oridonin promotes RSL3-induced ferroptosis in breast cancer cells by regulating the oxidative stress signaling pathway JNK/Nrf2/HO-1 [J]. Eur J Pharmacol. 2024; 974:176620.

[20] Ji Y, Li R, Tang G, et al. Integrative proteomics and metabolomics analyses reveals the regulation of autophagy and ferroptosis by RAB10 through Slc37a2/mTOR pathway in breast cancer [J]. Cell Mol Life Sci. 2025; 82(1): 275.

[21] Zhang H, Zhu S, Zhou H, et al. Identification of MTHFD2 as a prognostic biomarker and ferroptosis regulator in triple-negative breast cancer [J]. Front Oncol. 2023; 13:1098357.

[22] Hu S, Ma J, Su C, et al. Engineered exosome-like nanovesicles suppress tumor growth by reprogramming tumor microenvironment and promoting tumor ferroptosis [J]. Acta Biomater. 2021; 135: 567-581.

[23] Yang H, Li G, Zhang J, et al. A novel hollow iron nanoparticle system loading PEG-Fe(3)O(4) with C5a receptor antagonist for breast cancer treatment [J]. Front Immunol. 2024; 15:1466180.

[24] Gao Y, Huang Y, Zhao Y, et al. Cancer-associated fibroblast-secreted exosomal miR-454-3p inhibits lipid metabolism and ferroptosis in breast cancer by targeting ACSL4 [J]. Naunyn-Schmiedeberg's Arch Pharmacol. 2025; 398(4): 3925-3937.

[25] Qiao K, Huang Y, Ning S, et al. Camouflaged Nanozymes with Oxidation-Promoting Activities Triggering Ferroptosis for Radio-Immunotherapy [J]. Adv Sci (Weinh). 2025; 12(22):e2417370.

[26] Guo Y, Lv T, Li Z, et al. Acidity-activatable dynamic hybrid nanoplatforms derived from extracellular vesicles of M1 macrophages enhance cancer immunotherapy through synergistic triple immunotherapy [J]. J Nanobiotechnol. 2024; 22(1): 430.

[27] Dirat B, Bochet L, Dabek M, et al. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion [J]. Cancer Res. 2011; 71(7): 2455-2465.

[28] Balaban S, Shearer RF, Lee LS, et al. Adipocyte lipolysis links obesity to breast cancer growth: adipocyte-derived fatty acids drive breast cancer cell proliferation and migration [J]. Cancer & Metabolism. 2017; 5: 1.

[29] Magtanong L, Ko PJ, To M, et al. Exogenous Monounsaturated Fatty Acids Promote a Ferroptosis-Resistant Cell State [J]. Cell Chem Biol. 2019; 26(3): 420-432.e9.

[30] Liao K, Wen J, Liu Z, et al. The role of intratumoral microbiome in the occurrence, proliferation, metastasis of colorectal cancer and its underlying therapeutic strategies [J]. Ageing Res Rev. 2025; 111:102820.

[31] Hui S, Ghergurovich JM, Morscher RJ, et al. Glucose feeds the TCA cycle via circulating lactate [J]. Nature. 2017; 551(7678): 115-118.

[32] Bersuker K, Hendricks JM, Li Z, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis [J]. Nature. 2019; 575(7784): 688-692.

[33] Stockwell BR, Jiang X. The Chemistry and Biology of Ferroptosis [J]. Cell Chem Biol. 2020; 27(4): 365-375.

[34] Minokoshi Y, Kim YB, Peroni OD, et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase [J]. Nature. 2002; 415(6869): 339-343.

[35] Ouchi N, Kihara S, Arita Y, et al. Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway [J]. Circulation. 2000; 102(11): 1296-1301.

[36] Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase [J]. Nat Med. 2002; 8(11): 1288-1295.

[37] Ohashi K, Parker JL, Ouchi N, et al. Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype [J]. J Biol Chem. 2010; 285(9): 6153-6160.

[38] Lovren F, Pan Y, Quan A, et al. Adiponectin primes human monocytes into alternative anti-inflammatory M2 macrophages [J]. Am J Physiol Heart and Circulatory Physiol. 2010; 299(3): H656-H663.

[39] Brožová K, Hantusch B, Kenner L, et al. Spatial Proteomics for the Molecular Characterization of Breast Cancer [J]. Proteomes. 2023; 11(2): 17.

[40] Setayeshpour Y, Lee Y, Chi JT. Environmental Determinants of Ferroptosis in Cancer [J]. Cancers. 2023; 15(15): 3861.

[41] Wang W, Green M, Choi JE, et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy [J]. Nature. 2019; 569(7755): 270-274.

[42] Liao P, Wang W, Wang W, et al. CD8(+) T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4 [J]. Cancer Cell. 2022; 40(4): 365-378.e6.

[43] Chen X, Kang R, Kroemer G, et al. Ferroptosis in infection, inflammation, and immunity [J]. J Exp Med. 2021; 218(6):e20210518.

[44] Wang P, Lu YQ. Ferroptosis: A Critical Moderator in the Life Cycle of Immune Cells [J]. Front Immunol. 2022; 13: 877634.

[45] Nathan CF, Murray HW, Wiebe ME, et al. Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity [J]. J Exp Med. 1983; 158(3): 670-689.

[46] Recalcati S, Locati M, Marini A, et al. Differential regulation of iron homeostasis during human macrophage polarized activation [J]. Eur J Immunol. 2010; 40(3): 824-835.

[47] Li H, Yang P, Wang J, et al. HLF regulates ferroptosis, development and chemoresistance of triple-negative breast cancer by activating tumor cell-macrophage crosstalk [J]. J Hematol Oncol. 2022; 15(1): 2.

[48] Zhao Y, Liu Z, Liu G, et al. Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1 [J]. Cell Metab. 2023; 35(10): 1688-1703.e10.

[49] Zeng W, Zhang R, Huang P, et al. Ferroptotic Neutrophils Induce Immunosuppression and Chemoresistance in Breast Cancer [J]. Cancer Res. 2025; 85(3): 477-496.

[50] Castillo JG, Silveria S, Schirokauer L, et al. Selective disruption of lipid peroxide homeostasis in intratumoral regulatory T cells by targeting FSP1 enhances cancer immunity [J]. Sci Adv. 2026; 12(4):eaea3703.

[51] Li Y, Zhao Y. Reprogramming ferroptosis in MDSCs: For state-dependent immunotherapy combinations [J]. Biochimica et Biophysica Acta Reviews on Cancer. 2026; 1881(2):189571.

[52] Wu Q, Li B, Li Z, et al. Cancer-associated adipocytes: key players in breast cancer progression [J]. J Hematol Oncol. 2019; 12(1): 95.

[53] Reilly SM, Saltiel AR. Adapting to obesity with adipose tissue inflammation [J]. Nat Rev Endocrinol. 2017; 13(11): 633-643.

[54] Kohlgruber A, Lynch L. Adipose tissue inflammation in the pathogenesis of type 2 diabetes [J]. Curr Diab Rep. 2015; 15(11): 92.

[55] Pacella I, Procaccini C, Focaccetti C, et al. Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth [J]. Proc Nat Acad Sci USA. 2018; 115(28): E6546-e6555.

[56] Liu Y, Xu R, Gu H, et al. Metabolic reprogramming in macrophage responses [J]. Biomark Res. 2021; 9(1): 1.

[57] Xiao Y, Xu Y, Wang H, et al. HEBP2-governed glutamine competition between tumor and macrophages dictates immunotherapy efficacy in triple-negative breast cancer [J]. Cell Metab. 2025; 37(10): 2030-2047.e7.

[58] Closset L, Foy JP, Louadj L, et al. CD36 enhances sensitivity of triple negative breast cancer cells to palmitate-induced ferroptosis [J]. Cell Death Dis. 2026; 17(1): 219.

[59] Xu H, Ye D, Ren M, et al. Ferroptosis in the tumor microenvironment: perspectives for immunotherapy [J]. Trends Mol Med. 2021; 27(9): 856-867.

[60] Zhai X, Lin Y, Zhu L, et al. Ferroptosis in cancer immunity and immunotherapy: Multifaceted interplay and clinical implications [J]. Cytokine Growth Factor Rev. 2024; 75: 101-109.

[61] Dai E, Han L, Liu J, et al. Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein [J]. Autophagy. 2020; 16(11): 2069-2083.

[62] Hu J, Cui L, Hou B, et al. Ferroptosis in tumor associated immune cells: A double-edged sword against tumors [J]. Crit Rev Oncol Hematol. 2025; 212: 104818.

[63] Lu Y, Ge Y, Tu F, et al. In Situ Investigation of Intercellular Communication in Ferroptosis Integrated Scanning Electrochemical Microscopy with Microfluidic Devices [J]. ACS Sens. 2025; 10(5): 3559-3568.

[64] Li R, Liu Y, Pang B, et al. RAB10 mediates metabolic regulation of ferroptosis in breast Cancer and synergistically remodels the tumour immune microenvironment via macrophage M2 polarization [J]. Int Immunopharmacol. 2026; 172:116201.

[65] Wang L, Wang Y, Liu C, et al. The USP8/CEP55/CHMP6 Axis Orchestrates Triple-Negative Breast Cancer Progression by Regulating Ferroptosis and Macrophage M2 Polarization [J]. Clin Breast Cancer. 2026; 26(1): 317-329.e1.

[66] De Candia P, Prattichizzo F, Garavelli S, et al. The pleiotropic roles of leptin in metabolism, immunity, and cancer [J]. J Exp Med. 2021; 218(5):e20191593.

[67] Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease [J]. Cell. 2017; 171(2): 273-285.

[68] Sato S, Yamanaka T, Komori Y, et al. AdipoR1-AMPK axis suppresses breast cancer across molecular subtypes via multimodal cell death pathways, including ferroptosis and apoptosis [J]. Cell Death Dis. 2026; 17(1): 384.

[69] Fang Q, Fang Q, Cheng R, et al. CAPE activates AMPK and Foxo3 signaling to induce growth inhibition and ferroptosis in triple-negative breast cancer [J]. PLoS One. 2024; 19(12):e0315037.

[70] Zhang M, Chen H, Zhang L, et al. Cryptotanshinone instigates ferroptosis to inhibit the development of tamoxifen-resistant breast cancer via the AMPK induced BECN1-SLC7A11 complex axis [J]. Exp Cell Res. 2025; 451(2):114726.

[71] Keren L, Bosse M, Marquez D, et al. A Structured Tumor-Immune Microenvironment in Triple Negative Breast Cancer Revealed by Multiplexed Ion Beam Imaging [J]. Cell. 2018; 174(6): 1373-1387.e19.

[72] Jackson HW, Fischer JR, Zanotelli VRT, et al. The single-cell pathology landscape of breast cancer [J]. Nature. 2020; 578(7796): 615-620.

[73] Wu SZ, Al-Eryani G, Roden DL, et al. A single-cell and spatially resolved atlas of human breast cancers [J]. Nat Genet. 2021; 53(9): 1334-1347.

[74] Lo Iacono M, Modica C, Porcelli G, et al. Targeting of the Peritumoral Adipose Tissue Microenvironment as an Innovative Antitumor Therapeutic Strategy [J]. Biomolecules. 2022; 12(5): 702.

[75] Xu S, Gao W, Lin S, et al. Self-assembled nanoparticles overcoming hypoxic and acidic microenvironment to synergistically potentiate ferroptosis in triple-negative breast cancer [J]. Int J Pharm. 2026; 696:126853.

[76] Cui K, Wang K, Huang Z. Ferroptosis and the tumor microenvironment [J]. J Exp Clin Cancer Res. 2024; 43(1): 315.

[77] Hua Y, Yang S, Zhang Y, et al. Modulating ferroptosis sensitivity: environmental and cellular targets within the tumor microenvironment [J]. J Exp Clin Cancer Res. 2024; 43(1): 19.

[78] Glibetic N, Weichhaus M. Metabolic Regulation of Ferroptosis in Breast Cancer [J]. Int J Mol Sci. 2025; 26(19): 9686.

[79] Xu J, Lin X, Han T, et al. Regulation mechanism of ferroptosis and its research progress in tumor immunotherapy [J]. Front Mol Biosci. 2022; 9:1045548.

[80] Glibetic N, Weichhaus M. Metabolic Regulation of Ferroptosis in Breast Cancer [J]. Int J Mol Sci. 2025; 26: 9686.

[81] Lorito N, Subbiani A, Smiriglia A, et al. FADS1/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer [J]. EMBO Mol Med. 2024; 16(7): 1533-1559.

[82] Ackermann T, Shokry E, Deshmukh R, et al. Breast cancer secretes anti-ferroptotic MUFAs and depends on selenoprotein synthesis for metastasis [J]. EMBO Mol Med. 2024; 16(11): 2749-2774.

[83] Wu Z, Zhang F, Yang K, et al. CircSCD1 inhibits ferroptosis in breast Cancer through stabilizing SCD1 protein via deubiquitinase OTUB1 [J]. Sci Rep. 2025; 15(1):12351.

[84] Xie D, Jiang Y, Wang H, et al. Formononetin triggers ferroptosis in triple-negative breast cancer cells by regulating the mTORC1/SREBP1/SCD1 pathway [J]. Front Pharmacol. 2024; 15:1441105.

[85] Huang G, Cai Y, Ren M, et al. Salidroside sensitizes Triple-negative breast cancer to ferroptosis by SCD1-mediated lipogenesis and NCOA4-mediated ferritinophagy [J]. J Adv Res. 2025; 74: 589-607.

[86] Cassetta L, Pollard JW. Targeting macrophages: therapeutic approaches in cancer [J]. Nat Rev Drug Discovery. 2018; 17(12): 887-904.

[87] Xue C, Zhang H, Wang X, et al. Bio-inspired engineered ferritin-albumin nanocomplexes for targeted ferroptosis therapy [J]. J Control Release. 2022; 351: 581-596.

[88] Zhang W, Chen L, Dong Y, et al. In situ delivery of JPH203 via camptothecin-peptide conjugate nanoassemblies to trigger ferroptosis in triple-negative breast cancer [J]. J Control Release. 2026; 393:114829.

[89] Zhu X, Xie L, Liao Q, et al. Calcium phosphate-mineralized nanoplatform for enhanced ferroptosis and synergistic anti-PDL1 therapy in triple-negative breast cancer through multi-pathway targeting [J]. Acta Biomater. 2025; 204: 610-623.

[90] Wang YY, Zhang X, Xu XY, et al. A Bioinspired Exosomal Nanoplatform for Coordinated Sorafenib and MicroRNA Delivery to Sensitize Ferroptosis and Induce Immunoactivation in Triple-Negative Breast Cancer [J]. ACS Nano. 2026; 0(17): 13245-13269.

[91] Chen J, Ma L, Yin M, et al. FBR-NDs: a ferroptosis-inducing nanocomplex for targeted breast cancer therapy via immune modulation and redox-responsive drug delivery [J]. Breast Cancer Res. 2026; 28(1): 68.

[92] Gao J, Wang WQ, Pei Q, et al. Engineering nanomedicines through boosting immunogenic cell death for improved cancer immunotherapy [J]. Acta Pharmacol Sin. 2020; 41(7): 986-994.

[93] Buta M, Jeftic N, Besu I, et al. The Landscape of Ferroptosis-Related Gene Signatures as Molecular Stratification in Triple-Negative Breast Cancer [J]. Diagnostics (Basel, Switzerland). 2026; 16(3): 379.

[94] Qian Z, Jiang Y, Cai Y, et al. FASN inhibits ferroptosis in breast cancer via USP5 palmitoylation-dependent regulation of GPX4 deubiquitination [J]. J Exp Clin Cancer Res. 2025; 44(1): 289.

[95] Zheng P, Hu Z, Shen Y, et al. PSAT1 impairs ferroptosis and reduces immunotherapy efficacy via GPX4 hydroxylation [J]. Nat Chem Biol. 2025; 21(9): 1420-1432.

[96] Deng K, Li H. Role of ferroptosis on immunotherapy in breast cancer [J]. Mol Biol Rep. 2026; 53(1): 655.

[97] Liu Y, Chen S, Wan X, et al. Tryptophan 2,3-dioxygenase-positive matrix fibroblasts fuel breast cancer lung metastasis via kynurenine-mediated ferroptosis resistance of metastatic cells and T cell dysfunction [J]. Cancer Communications (London, England). 2024; 44(11): 1261-1286.

[98] Gong H, Li Y, Yang W, et al. PRODH2-Mediated Metabolism in the Bone Microenvironment Promotes Breast Cancer Metastasis [J]. Cancer Res. 2025; 85(21): 4198-4211.

[99] Dibra D, Xiong S, Moyer SM, et al. Mutant p53 protects triple-negative breast adenocarcinomas from ferroptosis in vivo [J]. Sci Adv. 2024; 10(7):eadk1835.

[100] Guo M, Wang YJ, Shi J, et al. Oxidative stress-induced ZEB1 acetylation drives a hybrid epithelial-mesenchymal phenotype and promotes lung metastasis in triple-negative breast cancer [J]. Redox Biol. 2025; 86: 103834.

[101] Nagpal A, Redvers RP, Ling X, et al. Neoadjuvant neratinib promotes ferroptosis and inhibits brain metastasis in a novel syngeneic model of spontaneous HER2(+ve) breast cancer metastasis [J]. Breast Cancer Research: BCR. 2019; 21(1): 94.

[102] Yang X, Li Y, Peng Y, et al. An integrative analysis of ASCL1 in breast cancer and inhibition of ASCL1 increases paclitaxel sensitivity by activating ferroptosis via the CREB1/GPX4 axis [J]. Front Immunol. 2025; 16:1546794.

[103] Liang X, Fang S, Xin Y, et al. Cascade-targeting copper homeostasis nano-regulators for mild-photothermal boosted cuproptosis/ferroptosis mediated breast cancer therapy [J]. J Nanobiotechnol. 2025; 23(1): 651.

[104] He Z, Long H, Ma H, et al. 4, 9-dihydroxy-α-lapachone as a potent antiproliferation agent for triple-negative breast cancer via ferroptosis [J]. Fitoterapia. 2025; 183:106567.

[105] He L, Ren W, Cheng W, et al. Arsenene-Vanadene nanodots co-activate Apoptosis/Ferroptosis for enhanced chemo-immunotherapy [J]. Acta Biomater. 2025; 196: 453-470.

[106] Wu S, Yang G, Wen X, et al. Aldo-keto Reductase 1B10 (AKR1B10) Suppresses Sensitivity of Ferroptosis in TNBC by Activating the AKT/GSK3β/Nrf2/GPX4 Axis [J]. Frontiers in Bioscience (Landmark edition). 2025; 30(6):36615.

[107] Wu K, Zhang W, Chen H, et al. An iron oxyhydroxide-based nanosystem sensitizes ferroptosis by a “Three-Pronged” strategy in breast cancer stem cells [J]. Acta Biomater. 2023; 160: 281-296.

[108] Zhang Q, Jiang J, Hu T, et al. Oxygen vacancy-rich CoSn(OH)(6)/FeS(2) heterostructure-based microneedles for combinatorial cancer therapy via activation of ferroptosis and apoptosis [J]. J Colloid Interface Sci. 2025; 700(Pt 3):138558.

[109] Huang H, Guo H, Liu J, et al. Dendrimer/metal-phenolic nanocomplexes encapsulating CuO(2) for targeted magnetic resonance imaging and enhanced ferroptosis/cuproptosis/chemodynamic therapy by regulating the tumor microenvironment [J]. Acta Biomater. 2024; 183: 252-263.

[110] Lin Z, Ling J, Omer AM, et al. Flexible Microneedle Platform for Synergistic Chemo/Photothermal Ferroptosis Therapy via P-Glycoprotein Inhibition in Breast Cancer [J]. ACS Appl Mater Interfaces. 2025; 17(30): 42807-42823.

[111] Tian Y, He X, Yuan Y, et al. TME-Responsive Nanoplatform with Glutathione Depletion for Enhanced Tumor-Specific Mild Photothermal/Gene/Ferroptosis Synergistic Therapy [J]. Int J Nanomed. 2024; 19: 9145-9160.

[112] Sankaranarayanan SA, Eswar K, Srivastava R, et al. In situ thermosensitive H(2)O(2)/NO self-sufficient hydrogel for photothermal ferroptosis of triple-negative breast cancer [J]. Nanoscale. 2024; 16(40): 18899-18909.

[113] Zhou W, Fan T, Yan Y, et al. A manganese-oxide nano-rambutan as the intrinsic modifier for hypericin delivery and triple-negative breast cancer treatment [J]. Int J Pharm. 2024; 666:124824.

[114] Hou YK, Zhang ZJ, Li RT, et al. Remodeling the Tumor Microenvironment with Core-Shell Nanosensitizer Featuring Dual-Modal Imaging and Multimodal Therapy for Breast Cancer [J]. ACS Appl Mater Interfaces. 2023; 15(2): 2602-2616.

[115] Tang Y, Zhang Q, Chen H, et al. A Integrated Molecule Based on Ferritin Nanoplatforms for Inducing Tumor Ferroptosis with the Synergistic Photo/Chemodynamic Treatment [J]. ACS Appl Mater Interfaces. 2025; 17(4): 5909-5920.

[116] Shi J, Cui G, Jin Y, et al. Glutathione-Depleted Photodynamic Nanoadjuvant for Triggering Nonferrous Ferroptosis to Amplify Radiotherapy of Breast Cancer [J]. Adv Healthcare Mater. 2024; 13(31):e2402474.

[117] Li R, Yuan H, Zhang C, et al. Induced Ferroptosis Pathway by Regulating Cellular Lipid Peroxidation With Peroxynitrite Generator for Reversing “Cold” Tumors [J]. Small (Weinheim an der Bergstrasse, Germany). 2024; 20(49):e2404807.

[118] Zheng B, Zhang H, Yu G, et al. Cascade Catalytic Nanozymes Induce Tumor Ca(2+) Overload and Ferroptosis by Reducing Energy Supply and Amplifying Oxidative Stress [J]. ACS Appl Mater Interfaces. 2025; 17(23): 33498-33512.

[119] You P, Lu F, Ouyang C, et al. Acidic Lysosome-Anchoring Croconium-Based Nanoplatform for Enhanced Triple-Mode Bioimaging and Fe(3+)-Triggered Tumor Synergistic Therapy [J]. ACS Appl Mater Interfaces. 2024; 16(35): 46066-46078.

[120] Zhang B, Liu H, Wang Y, et al. ROS-Responsive and Self-Catalytic Nanocarriers for a Combination of Chemotherapy and Reinforced Ferroptosis against Breast Cancer [J]. ACS Biomater Sci Eng. 2024; 10(10): 6352-6362.

[121] Mu M, Chen B, Li H, et al. Augmented the sensitivity of photothermal-ferroptosis therapy in triple-negative breast cancer through mitochondria-targeted nanoreactor [J]. J Control Release. 2024; 375: 733-744.

[122] Pan WL, Tan Y, Meng W, et al. Microenvironment-driven sequential ferroptosis, photodynamic therapy, and chemotherapy for targeted breast cancer therapy by a cancer-cell-membrane-coated nanoscale metal-organic framework [J]. Biomaterials. 2022; 283:121449.

[123] Tao B, Du R, Zhang X, et al. Engineering CAR-NK cell derived exosome disguised nano-bombs for enhanced HER2 positive breast cancer brain metastasis therapy [J]. J Control Release. 2023; 363: 692-706.

[124] Aishajiang R, Liu Z, Liang Y, et al. Concurrent Amplification of Ferroptosis and Immune System Activation Via Nanomedicine-Mediated Radiosensitization for Triple-Negative Breast Cancer Therapy [J]. Adv Sci (Weinh). 2025; 12(7):e2407833.

[125] Wu M, Zhang Z, Li D, et al. Integrating oxygen-boosted sonodynamic therapy and ferroptosis via engineered exosomes for effective cancer treatment [J]. Theranostics. 2025; 15(1): 68-85.

[126] Ye P, Wang C, Wen Y, et al. A positive-feedback loop suppresses TNBC tumour growth by remodeling tumour immune microenvironment and inducing ferroptosis [J]. Biomaterials. 2025; 315:122960.

[127] Pei M, Guan X, Hou X, et al. A GSH-consuming polymeric nanoparticles drives ferroptosis amplification and combines chemotherapy to amplify breast cancer treatment [J]. J Nanobiotechnol. 2025; 23(1): 497.

[128] Xing L, Liu XY, Zhou TJ, et al. Photothermal nanozyme-ignited Fenton reaction-independent ferroptosis for breast cancer therapy [J]. J Control Release. 2021; 339: 14-26.

[129] Tang L, Chen M, Wang D, et al. Doxorubicin and Iron-doped Mesoporous Silica Nanoparticles for Chemodynamic Therapy and Chemotherapy of Breast Cancer [J]. New Journal of Chemistry = Nouveau Journal de Chimie. 2024; 48(39): 17294-17309.

[130] Hu H, Zheng S, He C, et al. Radiotherapy-sensitized cancer immunotherapy via cGAS-STING immune pathway by activatable nanocascade reaction [J]. J Nanobiotechnol. 2024; 22(1): 234.

[131] Lin C, Sun J, Yang Y, et al. Peptide-based nanoassembly enhances ferroptosis in cancer to overcome paclitaxel resistance [J]. J Control Release. 2025; 384:113895.

[132] Xin L, Ning S, Wang H, et al. Tumor Microenvironment Responsive and Platelet Membrane Coated Polydopamine Nanoparticles for Cancer Radiosensitization by Inducing Cuproptosis [J]. Int J Nanomed. 2025; 20: 3643-3652.

[133] Han T, Sun Y, Jiang X, et al. Air bag-embedded MIL-101(Fe) metal-organic frameworks for an amplified tumor microenvironment activation loop through strategic delivery of iron ions and lentinan [J]. Theranostics. 2024; 14(15): 5883-5902.

[134] Yang Z, Deng L, Pan Z, et al. Oxygen-boosted nanodrug for amplified ferroptosis-photodynamic immunotherapy together with PD-1 checkpoint blockade against triple-negative breast cancer [J]. Colloids and Surfaces B, Biointerfaces. 2025; 255:114963.

[135] Guo S, Li Z, Zhou R, et al. MRI-Guided Tumor Therapy Based on Synergy of Ferroptosis, Immunosuppression Reversal and Disulfidptosis [J]. Small (Weinheim an der Bergstrasse, Germany). 2024; 20(29):e2309842.

[136] Deng X, Zhu Y, Dai Z, et al. A Bimetallic Nanomodulator to Reverse Immunosuppression via Sonodynamic-Ferroptosis and Lactate Metabolism Modulation [J]. Small (Weinheim an der Bergstrasse, Germany). 2024; 20(47):e2404580.

[137] Gu L, Sun Y, Bai T, et al. Functional nanozyme system for synergistic tumor immunotherapy via cuproptosis and ferroptosis activation [J]. J Nanobiotechnol. 2025; 23(1): 212.

[138] Zhu L, Chen M, Huang B, et al. Genomic Analysis Uncovers Immune Microenvironment Characteristics and Drug Sensitivity of Ferroptosis in Breast Cancer Brain Metastasis [J]. Front Genet. 2021; 12:819632.

[139] Cheng T, Wu Y, Liu Z, et al. CDKN2A-mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in triple-negative breast cancer [J]. Front Immunol. 2022; 13:970950.

[140] Wang W, Zhang J, Wang Y, et al. Identifies microtubule-binding protein CSPP1 as a novel cancer biomarker associated with ferroptosis and tumor microenvironment [J]. Comput Struct Biotechnol J. 2022; 20: 3322-3335.

[141] Zhang Y, Liu Y, Zhang M, et al. Clinical Relevance and Drug Modulation of PPAR Signaling Pathway in Triple-Negative Breast Cancer: A Comprehensive Analysis [J]. PPAR Research. 2024; 2024:4164906.

[142] Kumar T, Nee K, Wei R, et al. A spatially resolved single-cell genomic atlas of the adult human breast [J]. Nature. 2023; 620(7972): 181-191.

[143] Wang X, Wang Z, Liao Q, et al. Spatially resolved atlas of breast cancer uncovers intercellular machinery of venular niche governing lymphocyte extravasation [J]. Nat Commun. 2025; 16(1): 3348.

[144] Zhao L, Gu C, Gan Y, et al. Exosome-mediated siRNA delivery to suppress postoperative breast cancer metastasis [J]. J Control Release. 2020; 318: 1-15.

[145] Zhang P, Li C, Gao H, et al. Biomimetic hybrid membrane-coated nanoparticles loaded with rhein-iron complex enhance ferroptosis and immunotherapy for triple-negative breast cancer [J]. Materials Today Bio. 2026; 36:102747.

[146] Qiu Y, Wu H, Lin Z, et al. Magneto-photo-acoustic Nanotheranostics Orchestrate Ferroptosis-Immune Cross Talk for Spatiotemporally Amplified Triple-Negative Breast Cancer Therapy [J]. Biomater Res. 2025; 29: 0258.

[147] Friedmann Angeli JP, Krysko DV, Conrad M. Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion [J]. Nat Rev Cancer. 2019; 19(7): 405-414.

[148] Li J, Wu Y, Li Y, et al. Glutathione-Disrupting Nanotherapeutics Potentiate Ferroptosis for Treating Luminal Androgen Receptor-Positive Triple-Negative Breast Cancer [J]. ACS Nano. 2024; 18(39): 26585-26599.

[149] Monaco ME. ACSL4: biomarker, mediator and target in quadruple negative breast cancer [J]. Oncotarget. 2023; 14: 563-575.

[150] Chaudhary N, Mandal D, Choudhary BS, et al. Low-GPX4 drives a sustained drug-tolerant persister state in TNBC by a targetable adaptive FSP1 upregulation [J]. Redox Biol. 2025; 87:103864.

[151] Cao J, Zhou T, Wu T, et al. Targeting estrogen-regulated system x(c)(-) promotes ferroptosis and endocrine sensitivity of ER+ breast cancer [J]. Cell Death Dis. 2025; 16(1): 30.

[152] Ren Y, Zhang J, Duan M, et al. Targeting ZNF570 activates ferroptosis to reverse tamoxifen resistance in ER + breast cancer cells [J]. Naunyn-Schmiedeberg's Arch Pharmacol. 2026.

[153] Dong J, Shi T, Lin B, et al. Oncogenic role of the SLC7A13-SLC3A1 cystine transporter in human luminal breast cancer and its cryo-EM structure [J]. Protein & Cell. 2026; 17(2): 145-156.

[154] Bahnassy S, Stires H, Jin L, et al. Unraveling Vulnerabilities in Endocrine Therapy-Resistant HER2+/ER+ Breast Cancer [J]. Endocrinology. 2023; 164(12);bqad159.

[155] Gao J, Ye T, Miao H, et al. Antibody-functionalized iron-based nanoplatform for ferroptosis-augmented targeted therapy of HER2-positive breast cancer [J]. Bioactive Materials. 2025; 52: 702-718.

[156] Hu K, Qiu J, Hu Y, et al. Efficacy of FERscore in predicting sensitivity to ferroptosis inducers in breast cancer [J]. NPJ Breast Cancer. 2024; 10(1): 74.

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2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.