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BRD4 orchestrates the metabolic-epigenetic regulation of GM-CSF expression and secretion to drive PD-L1⁺ macrophage-mediated immune evasion in triple-negative breast cancer

Oncogene volume 45, pages 856–874 (2026) Cite this article

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Abstract

Immune checkpoint blockade targeting the PD-1/PD-L1 axis shows promise in triple-negative breast cancer (TNBC), yet durable responses are limited by immune escape. Here, we identified tumor-derived bromodomain-containing protein 4 (BRD4) as a critical mediator of tumor-associated macrophage (TAMs)-driven immune evasion in TNBC. Using syngeneic TNBC mouse models, we found that BRD4 promotes PD-L1 expression on TAMs by increasing GM-CSF production from tumor cells. Mechanistically, BRD4 binds to the GM-CSF promoter enriched with H4K8 lactylation (H4K8La) and H3K27 acetylation (H3K27Ac). BRD4 further sustains pyruvate and lactate pools via upregulation of PKM2, thereby amplifying H4K8La and H3K27Ac on the basis of modifications at the GM-CSF locus. Functionally, exogenous GM-CSF supplementation rescued impaired tumor growth and defective activation of TAMs caused by BRD4 inhibition, establishing a direct BRD4-GM-CSF-TAMs regulatory axis. Therapeutically, combined treatment with the BRD4 inhibitor JQ1 or the first bromodomain (BD1) selective inhibitor MS402 and an anti-GM-CSF antibody markedly suppressed TNBC progression and converted the tumor immune microenvironment from “cold” to “hot”. In conclusion, our study reveals a previously unrecognized metabolic-epigenetic mechanism through which BRD4 drives GM-CSF-dependent TAMs activation and immune evasion in TNBC. Targeting BRD4 in combination with GM-CSF blockade represents a promising therapeutic strategy to overcome immune resistance in this aggressive breast cancer subtype.

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Fig. 1: Tumor-derived BRD4 deficiency inhibits TAMs recruitment to the xenograft model.
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Fig. 2: BRD4 promotes M2-like TAMs accumulation.
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Fig. 3: Tumor-derived BRD4 is correlated with PD-L1+ and CD206+ macrophages in vivo.
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Fig. 4: Identification of GM-CSF as a direct target gene of BRD4.
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Fig. 5: BRD4 promotes the polarization of immunosuppressive TAMs through controlling GM-CSF expression.
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Fig. 6: BRD4 promotes GM-CSF expression through interaction with H3K27Ac and H4K8La.
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Fig. 7: Pyruvate metabolism is essential for BRD4-mediated modification of H3K27Ac and H4K8La.
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Fig. 8: The combination of JQ1 and GM-CSF antibody has synergistic antitumor effects.
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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Ligorio F, Vingiani A, Torelli T, Sposetti C, Drufuca L, Iannelli F. et al. Early downmodulation of tumor glycolysis predicts response to fasting-mimicking diet in triple-negative breast cancer patients. Cell Metab. 2024;37:330–344.

    Article  PubMed  Google Scholar 

  2. Rayson VC, Harris MA, Savas P, Hun ML, Virassamy B, Salgado R, et al. The anti-cancer immune response in breast cancer: current and emerging biomarkers and treatments. Trends Cancer. 2024;10:490–506.

    Article  PubMed  CAS  Google Scholar 

  3. Zhang J, Pan S, Jian C, Hao L, Dong J, Sun Q, et al. Immunostimulatory properties of chemotherapy in breast cancer: from immunogenic modulation mechanisms to clinical practice. Front Immunol. 2021;12:819405.

    Article  PubMed  CAS  Google Scholar 

  4. Sun J, Gui Y, Zhou S, Zheng XL. Unlocking the secrets of aging: Epigenetic reader BRD4 as the target to combatting aging-related diseases. J Adv Res. 2024;63:207–18.

    Article  PubMed  CAS  Google Scholar 

  5. Dong J, Li J, Li Y, Ma Z, Yu Y, Wang CY. Transcriptional super enhancers control cancer stemness and metastasis genes in squamous cell carcinoma. Nat Commun. 2021;12:3974.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Shi J, Vakoc CR. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell. 2014;54:728–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Shu S, Wu HJ, Ge JY, Zeid R, Harris IS, Jovanović B, et al. Synthetic lethal and resistance interactions with BET bromodomain inhibitors in triple-negative breast cancer. Mol Cell. 2020;78:1096–113.e8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Liu B, Liu X, Han L, Chen X, Wu X, Wu J, et al. BRD4-directed super enhancer organization of transcription repression programs links to chemotherapeutic efficacy in breast cancer. Proc Natl Acad Sci USA. 2022;119:e2109133119.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Lu L, Chen Z, Lin X, Tian L, Su Q, An P, et al. Inhibition of BRD4 suppresses the malignancy of breast cancer cells via regulation of Snail. Cell Death Differ. 2020;27:255–68.

    Article  PubMed  CAS  Google Scholar 

  10. Zhang Y, Xu B, Shi J, Li J, Lu X, Xu L, et al. BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways. Cell Oncol. 2020;43:1049–66.

    Article  CAS  Google Scholar 

  11. Spriano F, Stathis A, Bertoni F. Targeting BET bromodomain proteins in cancer: The example of lymphomas. Pharmacol Ther. 2020;215:107631.

    Article  PubMed  CAS  Google Scholar 

  12. Sarnik J, Popławski T, Tokarz P. BET Proteins as Attractive Targets for Cancer Therapeutics. Int J Mol Sci. 2021;22:11102.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Chu X, Tian Y, Lv C. Decoding the spatiotemporal heterogeneity of tumor-associated macrophages. Mol Cancer. 2024;23:150.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bied M, Ho WW, Ginhoux F, Blériot C. Roles of macrophages in tumor development: a spatiotemporal perspective. Cell Mol Immunol. 2023;20:983–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Jing W, Guo X, Wang G, Bi Y, Han L, Zhu Q, et al. Breast cancer cells promote CD169(+) macrophage-associated immunosuppression through JAK2-mediated PD-L1 upregulation on macrophages. Int Immunopharmacol. 2020;78:106012.

    Article  PubMed  CAS  Google Scholar 

  16. Xu J, Shi Q, Lou J, Wang B, Wang W, Niu J, et al. Chordoma recruits and polarizes tumor-associated macrophages by secreting CCL5 to promote malignant progression. J Immunother Cancer. 2023;11:e006808.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Mu J, Sun P, Ma Z, Sun P. BRD4 promotes tumor progression and NF-κB/CCL2-dependent tumor-associated macrophage recruitment in GIST. Cell Death Dis. 2019;10:935.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Tu M, Klein L, Espinet E, Georgomanolis T, Wegwitz F, Li X, et al. TNF-α-producing macrophages determine subtype identity and prognosis via AP1 enhancer reprogramming in pancreatic cancer. Nat Cancer. 2021;2:1185–203.

    Article  PubMed  CAS  Google Scholar 

  19. Li X, Fu Y, Yang B, Guo E, Wu Y, Huang J, et al. BRD4 Inhibition by AZD5153 promotes antitumor immunity via depolarizing M2 macrophages. Front Immunol. 2020;11:89.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Yin Y, Liu B, Cao Y, Yao S, Liu Y, Jin G, et al. Colorectal cancer-derived small extracellular vesicles promote tumor immune evasion by upregulating PD-L1 expression in tumor-associated macrophages. Adv Sci. 2022;9:2102620.

    Article  CAS  Google Scholar 

  21. Jiang X, Wang J, Lin L, Du L, Ding Y, Zheng F, et al. Macrophages promote pre-metastatic niche formation of breast cancer through aryl hydrocarbon receptor activity. Signal Transduct Target Ther. 2024;9:352.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Sprooten J, Vanmeerbeek I, Datsi A, Govaerts J, Naulaerts S, Laureano RS, et al. Lymph node and tumor-associated PD-L1(+) macrophages antagonize dendritic cell vaccines by suppressing CD8(+) T cells. Cell Rep Med. 2024;5:101377.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Raychaudhuri D, Singh P, Chakraborty B, Hennessey M, Tannir AJ, Byregowda S, et al. Histone lactylation drives CD8(+) T-cells metabolism and function. Nat Immunol. 2024;25:2140–51.

    Article  PubMed  CAS  Google Scholar 

  24. Yue SW, Liu HL, Su HF, Luo C, Liang HF, Zhang BX, et al. m6A-regulated tumor glycolysis: new advances in epigenetics and metabolism. Mol Cancer. 2023;22:137.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Yang J, Xu J, Wang W, Zhang B, Yu X, Shi S. Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther. 2023;8:210.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Wu SZ, Al-Eryani G, Roden DL, Junankar S, Harvey K, Andersson A, et al. A single-cell and spatially resolved atlas of human breast cancers. Nat Genet. 2021;53:1334–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Boac BM, Abbasi F, Ismail-Khan R, Xiong Y, Siddique A, Park H, et al. Expression of the BAD pathway is a marker of triple-negative status and poor outcome. Sci Rep. 2019;9:17496.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Maire V, Némati F, Richardson M, Vincent-Salomon A, Tesson B, Rigaill G, et al. Polo-like kinase 1: a potential therapeutic option in combination with conventional chemotherapy for the management of patients with triple-negative breast cancer. Cancer Res. 2013;73:813–23.

    Article  PubMed  CAS  Google Scholar 

  29. Győrffy B. Survival analysis across the entire transcriptome identifies biomarkers with the highest prognostic power in breast cancer. Comput Struct Biotechnol J. 2021;19:4101–9.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Lu D, Ni Z, Liu X, Feng S, Dong X, Shi X, et al. Beyond T Cells: Understanding the Role of PD-1/PD-L1 in Tumor-Associated Macrophages. J Immunol Res. 2019;2019:1919082.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hirayama AV, Wright JH, Smythe KS, Fiorenza S, Shaw AN, Gauthier J, et al. PD-L1(+) macrophage and tumor cell abundance and proximity to T cells in the pretreatment large B-cell lymphoma microenvironment impact CD19 CAR-T-cells immunotherapy efficacy. Hemasphere. 2024;8:e142.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Thorn M, Guha P, Cunetta M, Espat NJ, Miller G, Junghans RP, et al. Tumor-associated GM-CSF overexpression induces immunoinhibitory molecules via STAT3 in myeloid-suppressor cells infiltrating liver metastases. Cancer Gene Ther. 2016;23:188–98.

    Article  PubMed  CAS  Google Scholar 

  34. Guha P, Gardell J, Darpolor J, Cunetta M, Lima M, Miller G, et al. STAT3 inhibition induces Bax-dependent apoptosis in liver tumor myeloid-derived suppressor cells. Oncogene. 2019;38:533–48.

    Article  PubMed  CAS  Google Scholar 

  35. Guo J, Zheng Q, Peng Y. BET proteins: Biological functions and therapeutic interventions. Pharmacol Ther. 2023;243:108354.

    Article  PubMed  CAS  Google Scholar 

  36. Zhang F, Zhou J, Lu P, Zhang X, Yang L, Wu J, et al. Lactylation of histone by BRD4 regulates astrocyte polarization after experimental subarachnoid hemorrhage. J Neuroinflammation. 2024;21:186.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Hogg SJ, Motorna O, Cluse LA, Johanson TM, Coughlan HD, Raviram R, et al. Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition. Mol Cell. 2021;81:2183–200.e13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Gu M, Ren B, Fang Y, Ren J, Liu X, Wang X, et al. Epigenetic regulation in cancer. MedComm (2020). 2024;5:e495.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Jemal M, Getinet M, Amare GA, Tegegne BA, Baylie T, Mengistu EF, et al. Nonmetabolic enzyme function of pyruvate kinase M2 in breast cancer. Front Oncol. 2024;14:1450325.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Upadhyay S, Khan S, Hassan MI. Exploring the diverse role of pyruvate kinase M2 in cancer: Navigating beyond glycolysis and the Warburg effect. Biochim Biophys Acta Rev Cancer. 2024;1879:189089.

    Article  PubMed  CAS  Google Scholar 

  41. Jiang G, Deng W, Liu Y, Wang C. General mechanism of JQ1 in inhibiting various types of cancer. Mol Med Rep. 2020;21:1021–34.

    PubMed  PubMed Central  CAS  Google Scholar 

  42. Zhang M, Li Y, Zhang Z, Zhang X, Wang W, Song X, et al. BRD4 Protein as a Target for Lung Cancer and Hematological Cancer Therapy: A Review. Curr Drug Targets. 2023;24:1079–92.

    Article  PubMed  CAS  Google Scholar 

  43. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146:904–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Peirs S, Frismantas V, Matthijssens F, Van Loocke W, Pieters T, Vandamme N, et al. Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia. Leukemia. 2017;31:2037–47.

    Article  PubMed  CAS  Google Scholar 

  45. Wan M, Pan S, Shan B, Diao H, Jin H, Wang Z, et al. Lipid metabolic reprograming: the unsung hero in breast cancer progression and tumor microenvironment. Molecular Cancer. 2025;24:61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Zhou JX, Agborbesong E, Li LX, Li X. Bromodomain Protein BRD4-Mediated Mutant p53 Transcription Promotes TNBC Progression. Int J Mol Sci. 2022;23:15163.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Yin M, Guo Y, Hu R, Cai WL, Li Y, Pei S, et al. Potent BRD4 inhibitor suppresses cancer cell-macrophage interaction. Nat Commun. 2020;11:1833.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Jing X, Shao S, Zhang Y, Luo A, Zhao L, Zhang L, et al. BRD4 inhibition suppresses PD-L1 expression in triple-negative breast cancer. Exp Cell Res. 2020;392:112034.

    Article  PubMed  CAS  Google Scholar 

  49. Liu Y, Cai L, Wang H, Yao L, Wu Y, Zhang K. et al. BRD4 promotes immune escape of glioma cells by upregulating PD-L1 expression. J Neuroonco. 2024;171:669–679.

    Article  Google Scholar 

  50. Wang J, Xu Y, Rao X, Zhang R, Tang J, Zhang D, et al. BRD4-IRF1 axis regulates chemoradiotherapy-induced PD-L1 expression and immune evasion in non-small cell lung cancer. Clin Transl Med. 2022;12:e718.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Hartley GP, Chow L, Ammons DT, Wheat WH, Dow SW. Programmed cell death ligand 1 (PD-L1) signaling regulates macrophage proliferation and activation. Cancer Immunol Res. 2018;6:1260–73.

    Article  PubMed  CAS  Google Scholar 

  52. Kim S, Jeon SH, Han MG, Kang MH, Kim IA. BRD4 inhibition enhances the antitumor effects of radiation therapy in a murine breast cancer model. Int J Mol Sci. 2023;24:13062.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Sheng D, Ma W, Zhang R, Zhou L, Deng Q, Tu J, et al. Ccl3 enhances docetaxel chemosensitivity in breast cancer by triggering proinflammatory macrophage polarization. J Immunother Cancer. 2022;10:e003793.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Chen Y, Li F, Hua M, Liang M, Song C. Role of GM-CSF in lung balance and disease. Front Immunol. 2023;14:1158859.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Shibata Y, Berclaz PY, Chroneos ZC, Yoshida M, Whitsett JA, Trapnell BC. GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1. Immunity. 2001;15:557–67.

    Article  PubMed  CAS  Google Scholar 

  56. Owen JL, Torroella-Kouri M, Handel-Fernandez ME, Iragavarapu-Charyulu V. GM-CSF upregulates the expression of CCL2 by T lymphocytes in mammary tumor-bearing mice. Int J Mol Med. 2007;20:129–36.

    PubMed  CAS  Google Scholar 

  57. Bagratuni T, Mavrianou N, Gavalas NG, Tzannis K, Arapinis C, Liontos M, et al. JQ1 inhibits tumor growth in combination with cisplatin and suppresses JAK/STAT signaling pathway in ovarian cancer. Eur J Cancer. 2020;126:125–35.

    Article  PubMed  CAS  Google Scholar 

  58. Rong QX, Wang F, Guo ZX, Hu Y, An SN, Luo M, et al. GM-CSF mediates immune evasion via upregulation of PD-L1 expression in extranodal natural killer/T-cell lymphoma. Mol Cancer. 2021;20:80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Leal AS, Williams CR, Royce DB, Pioli PA, Sporn MB, Liby KT. Bromodomain inhibitors, JQ1 and I-BET 762, as potential therapies for pancreatic cancer. Cancer Lett. 2017;394:76–87.

    Article  PubMed  CAS  Google Scholar 

  60. Chen Q, Yang B, Liu X, Zhang XD, Zhang L, Liu T. Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents. Theranostics. 2022;12:4935–48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574:575–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Hu XT, Wu XF, Xu JY, Xu X. Lactate-mediated lactylation in human health and diseases: progress and remaining challenges. J Adv Res. 2024;75:229–248.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Zhai G, Niu Z, Jiang Z, Zhao F, Wang S, Chen C, et al. DPF2 reads histone lactylation to drive transcription and tumorigenesis. Proceedings of the National Academy of Sciences. 2024;121:e2421496121.

    Article  CAS  Google Scholar 

  64. Li F, Si W, Xia L, Yin D, Wei T, Tao M, et al. Positive feedback regulation between glycolysis and histone lactylation drives oncogenesis in pancreatic ductal adenocarcinoma. Mol Cancer. 2024;23:90.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Dai X, Lv X, Thompson EW, Ostrikov KK. Histone lactylation: epigenetic mark of glycolytic switch. Trends Genet. 2022;38:124–7.

    Article  PubMed  CAS  Google Scholar 

  66. Fan P, Wang B, Meng Z, Zhao J, Jin X. PES1 is transcriptionally regulated by BRD4 and promotes cell proliferation and glycolysis in hepatocellular carcinoma. Int J Biochem Cell Biol. 2018;104:1–8.

    Article  PubMed  CAS  Google Scholar 

  67. Shorstova T, Foulkes WD, Witcher M. Achieving clinical success with BET inhibitors as anti-cancer agents. Br J Cancer. 2021;124:1478–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Wahi A, Manchanda N, Jain P, Jadhav HR. Targeting the epigenetic reader “BET” as a therapeutic strategy for cancer. Bioorg Chem. 2023;140:106833.

    Article  PubMed  CAS  Google Scholar 

  69. Bhattacharya P, Budnick I, Singh M, Thiruppathi M, Alharshawi K, Elshabrawy H, et al. Dual Role of GM-CSF as a Pro-Inflammatory and a Regulatory Cytokine: Implications for Immune Therapy. J Interferon Cytokine Res. 2015;35:585–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Gallina G, Dolcetti L, Serafini P, De Santo C, Marigo I, Colombo MP, et al. Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J Clin Invest. 2006;116:2777–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Lazarus HM, Ragsdale CE, Gale RP, Lyman GH. Sargramostim (rhu GM-CSF) as Cancer Therapy (Systematic Review) and An Immunomodulator. A Drug Before Its Time?. Front Immunol. 2021;12:706186.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Ruffolo LI, Jackson KM, Kuhlers PC, Dale BS, Figueroa Guilliani NM, Ullman NA, et al. GM-CSF drives myelopoiesis, recruitment and polarization of tumor-associated macrophages in cholangiocarcinoma and systemic blockade facilitates antitumour immunity. Gut. 2022;71:1386–98.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (82573085, 82203159, 82172775 and 82472979), the Anhui Provincial Special Program of Clinical Medical Science (202304295107020055, 202304295107020052 and 202304295107020000), the Scientific Research Innovation Team Project of Anhui Colleges and Universities (grant no. 2022AH010077), the Science and Research Project from the Health Commission of Anhui Province (grant no. AHWJ2023A10140), the Scientific Research Start-up the China Postdoctoral Science Foundation (2025T180660), and the Funds of The First Affiliated Hospital of USTC (RC2021122).

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Authors and Affiliations

  1. Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China

    Haizhou Diao, Yan Zhang, Hui Hua, Menghao Dong, Wei Jin, Jian Chen, Benjie Shan, Yueyue Cao, Xinghua Han, Yueyin Pan & Jinguo Zhang

  2. Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China

    Haizhou Diao, Yan Zhang, Hui Hua, Menghao Dong, Yueyue Cao, Yueyin Pan & Jinguo Zhang

  3. Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China

    Jingxiong Chen

  4. Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA

    Xiuwei Yang

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Contributions

HD, JZ and XY participated in the conception and design of the experiments. HD and JZ performed the experiments and wrote the manuscript. YZ, HH and YC helped with the in vivo research. HD analyzed the data. Jingxiong. C, Jian. C. performed the bioinformatics analysis. YP and JZ supervised the project. WJ, HD, BS, M.D. and XY wrote the manuscript. All the authors read and approved the final article and take responsibility for its content.

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Correspondence to Xinghua Han, Xiuwei Yang, Yueyin Pan or Jinguo Zhang.

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Diao, H., Chen, J., Zhang, Y. et al. BRD4 orchestrates the metabolic-epigenetic regulation of GM-CSF expression and secretion to drive PD-L1⁺ macrophage-mediated immune evasion in triple-negative breast cancer. Oncogene 45, 856–874 (2026). https://doi.org/10.1038/s41388-026-03681-4

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