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Activated MAFB in ovarian cancer promotes cytoskeletal remodeling and immune microenvironment suppression by interfering with m6A modifications through WTAP competition

Oncogene volume 44, pages 3799–3815 (2025)Cite this article

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A Correction to this article was published on 05 December 2025

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Abstract

The tumor microenvironment (TME) coordinates cancer progression through complex transcriptional networks, but the molecular mechanisms controlling immune evasion in ovarian cancer remain elusive. Here, by integrating immune dysfunction characteristics across multiple clinical cohorts and single-cell transcriptomics, we identified MAFB as a major regulator of ovarian cancer progression. MAFB expression exhibited stage-dependent elevation and was associated with immune checkpoint characteristics. Mechanistically, MAFB competitively binds to the core component WTAP of the m6A methyltransferase complex, thereby antagonizing the degradation of target gene mRNAs (WNT5A, CD55). This atypical regulatory axis leads to persistent expression of the target genes, further coordinating tumor cell invasiveness and immune landscape remodeling through cytoskeletal protein reorganization, M2 macrophage polarization, and regulatory T cell infiltration. Correlative analyses in patient cohorts and therapeutic effects in preclinical models support the clinical relevance of this pathway. Our findings uncover a novel mechanism by which MAFB promotes ovarian cancer progression through cytoskeletal remodeling and immune suppression, connecting transcriptional regulation with epitranscriptomic modifications, and identify the MAFB-WTAP-CD55 axis as a potential therapeutic target in ovarian cancer.

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Fig. 1: MAFB is associated with immune dysfunction and metastasis in ovarian cancer.
Fig. 2: MAFB promotes TGF-β-dependent metastasis and microenvironment-supported tumor growth.
Fig. 3: MAFB promotes metastasis by activating the WNT5A/PCP pathway to remodel the cytoskeleton.
Fig. 4: MAFB promotes immune suppression by enhancing macrophage polarization and regulatory T cell activation.
Fig. 5: MAFB promotes immune suppression through CD55-mediated intercellular communication.
Fig. 6: MAFB competitively binds to WTAP and influences m6A modification of target genes.
Fig. 7: Molecular mechanism of MAFB-WTAP competitive binding.
Fig. 8: Schematic representation of MAFB-mediated tumor progression through cytoskeletal remodeling and immune regulation.

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Data availability

The datasets used and analyzed during the current study are available as follows: Public Databases: The Cancer Genome Atlas (TCGA) ovarian cancer dataset is available through the GDC Data Portal (https://portal.gdc.cancer.gov/). GTEx normal ovarian tissue data can be accessed through the GTEx Portal (https://gtexportal.org/). Single-cell RNA sequencing data from GSE180661, MeRIP-seq data (GSE55572), and additional ovarian cancer cohort data used in this study (GSE17260, GSE26712, GSE32062, GSE49997, GSE51088, GSE63885, GSE9891) is available in the Gene Expression Omnibus (GEO) database. Raw Data: The sequencing data generated in this study has been deposited in the Gene Expression Omnibus (GEO) database, with the accession number GSE281103. Additional Materials: Additional data that support the findings of this study are available from the corresponding author upon reasonable request.

Change history

  • 05 December 2025

    The original online version of this article was revised: In this article the order of affiliations has been exchanged. The correct order is 1. Department of Gynecology and Obstetrics, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. 2. Department of Immunology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China.

  • 05 December 2025

    A Correction to this paper has been published: https://doi.org/10.1038/s41388-025-03656-x

References

  1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74:12–49.

    PubMed  Google Scholar 

  2. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–63.

    PubMed  Google Scholar 

  3. Bowtell DD, Böhm S, Ahmed AA, Aspuria PJ, Bast RC Jr, Beral V, et al. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer. Nat Rev Cancer. 2015;15:668–79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Silva R, Glennon K, Metoudi M, Moran B, Salta S, Slattery K, et al. Unveiling the epigenomic mechanisms of acquired platinum-resistance in high-grade serous ovarian cancer. Int J Cancer. 2023;153:120–32.

    Article  PubMed  CAS  Google Scholar 

  5. Lheureux S, Gourley C, Vergote I, Oza AM. Epithelial ovarian cancer. Lancet. 2019;393:1240–53.

    Article  PubMed  Google Scholar 

  6. Matulonis UA, Sood AK, Fallowfield L, Howitt BE, Sehouli J, Karlan BY. Ovarian cancer. Nat Rev Dis Prim. 2016;2:16061.

    Article  PubMed  Google Scholar 

  7. Menon U, Griffin M, Gentry-Maharaj A. Ovarian cancer screening-current status, future directions. Gynecol Oncol. 2014;132:490–5.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D’Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 2015;5:1137–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Zhang AW, McPherson A, Milne K, Kroeger DR, Hamilton PT, Miranda A, et al. Interfaces of malignant and immunologic clonal dynamics in ovarian cancer. Cell. 2018;173:1755–69.e22.

    Article  PubMed  CAS  Google Scholar 

  10. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12:31–46.

    Article  PubMed  CAS  Google Scholar 

  12. Lu X, Ji C, Jiang L, Zhu Y, Zhou Y, Meng J, et al. Tumour microenvironment-based molecular profiling reveals ideal candidates for high-grade serous ovarian cancer immunotherapy. Cell Prolif. 2021;54:e12979.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24:541–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Lambert SA, Jolma A, Campitelli LF, Das PK, Yin Y, Albu M, et al. The human transcription factors. Cell. 2018;172:650–65.

    Article  PubMed  CAS  Google Scholar 

  15. Saint-André V, Federation AJ, Lin CY, Abraham BJ, Reddy J, Lee TI, et al. Models of human core transcriptional regulatory circuitries. Genome Res. 2016;26:385–96.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lee TI, Young RA. Transcriptional regulation and its misregulation in disease. Cell. 2013;152:1237–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Bhagwat AS, Vakoc CR. Targeting transcription factors in cancer. Trends Cancer. 2015;1:53–65.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Carro MS, Lim WK, Alvarez MJ, Bollo RJ, Zhao X, Snyder EY, et al. The transcriptional network for mesenchymal transformation of brain tumours. Nature. 2010;463:318–25.

    Article  PubMed  CAS  Google Scholar 

  19. Eychène A, Rocques N, Pouponnot C. A new MAFia in cancer. Nat Rev Cancer. 2008;8:683–93.

    Article  PubMed  Google Scholar 

  20. Sieweke MH, Tekotte H, Frampton J, Graf T. MafB is an interaction partner and repressor of Ets-1 that inhibits erythroid differentiation. Cell. 1996;85:49–60.

    Article  PubMed  CAS  Google Scholar 

  21. Kelly LM, Englmeier U, Lafon I, Sieweke MH, Graf T. MafB is an inducer of monocytic differentiation. EMBO J. 2000;19:1987–97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Jiang P, Gu S, Pan D, Fu J, Sahu A, Hu X, et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med. 2018;24:1550–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Fu J, Li K, Zhang W, Wan C, Zhang J, Jiang P, et al. Large-scale public data reuse to model immunotherapy response and resistance. Genome Med. 2020;12:21.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Aibar S, González-Blas CB, Moerman T, Huynh-Thu VA, Imrichova H, Hulselmans G, et al. SCENIC: single-cell regulatory network inference and clustering. Nat Methods. 2017;14:1083–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Jin S, Plikus MV, Nie Q. CellChat for systematic analysis of cell-cell communication from single-cell transcriptomics. Nat Protoc. 2025;20:180–219.

  26. Schwartz S, Mumbach MR, Jovanovic M, Wang T, Maciag K, Bushkin GG, et al. Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5’ sites. Cell Rep. 2014;8:284–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Hamada M, Nakamura M, Tran MT, Moriguchi T, Hong C, Ohsumi T, et al. MafB promotes atherosclerosis by inhibiting foam-cell apoptosis. Nat Commun. 2014;5:3147.

    Article  PubMed  Google Scholar 

  28. Kim H. The transcription factor MafB promotes anti-inflammatory M2 polarization and cholesterol efflux in macrophages. Sci Rep. 2017;7:7591.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Asem MS, Buechler S, Wates RB, Miller DL, Stack MS. Wnt5a signaling in cancer. Cancers. 2016;8:79.

  30. Bueno MLP, Saad STO, Roversi FM. WNT5A in tumor development and progression: a comprehensive review. Biomed Pharmacother. 2022;155:113599.

    Article  PubMed  CAS  Google Scholar 

  31. Tang Q, Li L, Wang Y, Wu P, Hou X, Ouyang J, et al. RNA modifications in cancer. Br J Cancer. 2023;129:204–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Su S, Li S, Deng T, Gao M, Yin Y, Wu B, et al. Cryo-EM structures of human m(6)A writer complexes. Cell Res. 2022;32:982–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Jiang X, Liu B, Nie Z, Duan L, Xiong Q, Jin Z, et al. The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther. 2021;6:74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Moriguchi T, Hamada M, Morito N, Terunuma T, Hasegawa K, Zhang C, et al. MafB is essential for renal development and F4/80 expression in macrophages. Mol Cell Biol. 2006;26:5715–27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Artner I, Blanchi B, Raum JC, Guo M, Kaneko T, Cordes S, et al. MafB is required for islet beta cell maturation. Proc Natl Acad Sci USA. 2007;104:3853–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Boersma-Vreugdenhil GR, Kuipers J, Van Stralen E, Peeters T, Michaux L, Hagemeijer A, et al. The recurrent translocation t(14;20)(q32;q12) in multiple myeloma results in aberrant expression of MAFB: a molecular and genetic analysis of the chromosomal breakpoint. Br J Haematol. 2004;126:355–63.

    Article  PubMed  CAS  Google Scholar 

  37. Yang LS, Zhang XJ, Xie YY, Sun XJ, Zhao R, Huang QH. SUMOylated MAFB promotes colorectal cancer tumorigenesis. Oncotarget. 2016;7:83488–501.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Yang W, Lan X, Li D, Li T, Lu S. MiR-223 targeting MAFB suppresses proliferation and migration of nasopharyngeal carcinoma cells. BMC Cancer. 2015;15:461.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Chen Y, Wang T, Huang M, Liu Q, Hu C, Wang B, et al. MAFB promotes cancer stemness and tumorigenesis in osteosarcoma through a Sox9-mediated positive feedback loop. Cancer Res. 2020;80:2472–83.

    Article  PubMed  CAS  Google Scholar 

  40. Maura F, Bergsagel PL. Molecular pathogenesis of multiple myeloma: clinical implications. Hematol Oncol Clin North Am. 2024;38:267–79.

    Article  PubMed  Google Scholar 

  41. Kikuchi A, Yamamoto H, Sato A, Matsumoto S. Wnt5a: its signalling, functions and implication in diseases. Acta Physiol. 2012;204:17–33.

    Article  CAS  Google Scholar 

  42. Yang Y, Topol L, Lee H, Wu J. Wnt5a and Wnt5b exhibit distinct activities in coordinating chondrocyte proliferation and differentiation. Development. 2003;130:1003–15.

    Article  PubMed  CAS  Google Scholar 

  43. Uehara S, Udagawa N, Kobayashi Y. Non-canonical Wnt signals regulate cytoskeletal remodeling in osteoclasts. Cell Mol Life Sci. 2018;75:3683–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Bharti R, Dey G, Lin F, Lathia J, Reizes O. CD55 in cancer: complementing functions in a non-canonical manner. Cancer Lett. 2022;551:215935.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Dho SH, Lim JC, Kim LK. Beyond the role of CD55 as a complement component. Immune Netw. 2018;18:e11.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Alizadeh H, Akbarabadi P, Dadfar A, Tareh MR, Soltani B. A comprehensive overview of ovarian cancer stem cells: correlation with high recurrence rate, underlying mechanisms, and therapeutic opportunities. Mol Cancer. 2025;24:135.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Guo T, Xu J. Cancer-associated fibroblasts: a versatile mediator in tumor progression, metastasis, and targeted therapy. Cancer Metastasis Rev. 2024;43:1095–116.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Li Z, Sun C, Qin Z. Metabolic reprogramming of cancer-associated fibroblasts and its effect on cancer cell reprogramming. Theranostics. 2021;11:8322–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Kennel KB, Bozlar M, De Valk AF, Greten FR. Cancer-associated fibroblasts in inflammation and antitumor immunity. Clin Cancer Res. 2023;29:1009–16.

    Article  PubMed  CAS  Google Scholar 

  50. Zhao BS, Roundtree IA, He C. Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol. 2017;18:31–42.

    Article  PubMed  CAS  Google Scholar 

  51. Huang H, Weng H, Chen J. m(6)A modification in coding and non-coding RNAs: roles and therapeutic implications in cancer. Cancer Cell. 2020;37:270–88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. An Y, Duan H. The role of m6A RNA methylation in cancer metabolism. Mol Cancer. 2022;21:14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Oerum S, Meynier V, Catala M, Tisné C. A comprehensive review of m6A/m6Am RNA methyltransferase structures. Nucleic Acids Res. 2021;49:7239–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Wang T, Kong S, Tao M, Ju S. The potential role of RNA N6-methyladenosine in cancer progression. Mol Cancer. 2020;19:88.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Estrada-Capetillo L, Aragoneses-Fenoll L, Domínguez-Soto Á, Fuentelsaz-Romero S, Nieto C, Simón-Fuentes M, et al. CD28 is expressed by macrophages with anti-inflammatory potential and limits their T-cell activating capacity. Eur J Immunol. 2021;51:824–34.

    Article  PubMed  CAS  Google Scholar 

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Funding

This study was supported by the “Chongqing Talents Program” of the Chongqing Municipal People’s Government (No. cstc2022ycjh-bgzxm0062).

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Author notes

  1. These authors contributed equally: Qinke Li, Siying Zhang, Min Wang.

Authors and Affiliations

  1. Department of Gynecology and Obstetrics, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Qinke Li, Siying Zhang, Min Wang, Qiang Yi, Hang Xu, Jinlong Wang & Zhu Yang

  2. Department of Immunology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China

    Qinke Li, Siying Zhang & Qiang Yi

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  1. Qinke Li
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Contributions

YZ and QL conceptualized and designed the study. QL, SZ, and MW performed data curation, analysis, and interpretation. QL, QY, and JW conducted the investigation and assisted with methodology. YZ supervised the project and acquired funding and resources. QL, HX, SZ, and QY developed the software and created visualizations. QL and SZ drafted the original manuscript. ZY provided critical revision of the manuscript for important intellectual content. All authors read and approved the final manuscript.

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Correspondence to Zhu Yang.

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The authors declare no competing interests.

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The study was carried out in compliance with the ARRIVE guidelines and the institutional guidelines for the care and use of animals. All animal experiments were conducted in accordance with the guidelines of the Animal Ethics Committee of Chongqing Medical University and were approved by the institutional review board (Approval No. IACUC-CQMU-2024-02035). Animals were housed and cared for in accordance with the Guide for the Care and Use of Laboratory Animals of Chongqing Medical University. All efforts were made to minimize animal suffering and reduce the number of animals used.

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Li, Q., Zhang, S., Wang, M. et al. Activated MAFB in ovarian cancer promotes cytoskeletal remodeling and immune microenvironment suppression by interfering with m6A modifications through WTAP competition. Oncogene 44, 3799–3815 (2025). https://doi.org/10.1038/s41388-025-03522-w

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