Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Cellular and Molecular Biology

The novel role of DUSP4 in suppressing ferroptosis and promoting cytotoxicity of CD8+ T cells in MSI colorectal cancer

British Journal of Cancer volume 133, pages 1096–1110 (2025)Cite this article

Subjects

Abstract

Background

Microsatellite instable (MSI) colorectal cancer (CRC) has distinct features that distinguish it from microsatellite stable CRC. While ferroptosis may play a role in the development of MSI CRC, its mechanisms remain unclear.

Methods

Ferroptosis was assessed via the detection of lipid peroxidation, malondialdehyde, 4-hydroxy-2-nonenal, and intracellular Fe2+, etc. Phosphoproteomic analysis, cytokine array, and flow cytometry were performed to explore the regulation of CD8+ T cell infiltration.

Results

Dual specificity phosphatase 4 (DUSP4) suppressed ferroptosis in MSI CRC cells by reducing lipid peroxidation and inhibiting intracellular Fe2+ accumulation. Mechanistic studies showed that DUSP4 downregulated the expression of transferrin receptor (TFRC), which was transcriptionally regulated by c-MYC. In addition, a positive correlation was observed between the infiltration of CD8+ T cells in CRC tissues and the expression of DUSP4 in cancer cells. Mechanistically, DUSP4 dephosphorylated cyclin-dependent kinase 7 (CDK7) and promoted C-X-C Motif chemokine ligand 16 (CXCL16) expression, resulting in an increased infiltration of CD8+ T cells. Importantly, the combination of a CDK7 inhibitor and anti-programmed cell death protein-1 therapy demonstrated a synergistic therapeutic effect in MSI CRC.

Conclusion

DUSP4 acts as a negative regulator of ferroptosis and a positive regulator of CD8+ T cell infiltration in MSI CRC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The reduced ferroptosis level in MSI CRC is correlated with the expression of DUSP4.
Fig. 2: DUSP4 inhibits ferroptosis and decreases intracellular Fe2+ level in MSI CRC cells.
Fig. 3: DUSP4 reduces ferroptosis by inhibiting TFRC expression in MSI CRC cells.
Fig. 4: DUSP4 inhibits TFRC expression via downregulating c-MYC in MSI CRC cells.
Fig. 5: DUSP4 is associated with an increased CD8+ T cell infiltration in MSI CRC and potentiates the effects of anti-PD-1 immunotherapy.
Fig. 6: DUSP4 promotes CXCL16 expression in MSI CRC cells.
Fig. 7: DUSP4 binds to and dephosphorylates CDK7 in MSI CRC cells.
Fig. 8: Graphic abstract of this study.

Similar content being viewed by others

Data availability

The datasets used and/or analysed, and materials used during the current study, are available from the corresponding authors upon reasonable request.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    PubMed  Google Scholar 

  2. Nguyen LH, Goel A, Chung DC. Pathways of colorectal carcinogenesis. Gastroenterology. 2020;158:291–302.

    CAS  PubMed  Google Scholar 

  3. Franke AJ, Skelton WP, Starr JS, Parekh H, Lee JJ, Overman MJ, et al. Immunotherapy for colorectal cancer: a review of current and novel therapeutic approaches. J Natl Cancer Inst. 2019;111:1131–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Battaglin F, Naseem M, Lenz HJ, Salem ME. Microsatellite instability in colorectal cancer: overview of its clinical significance and novel perspectives. Clin Adv Hematol Oncol. 2018;16:735–45.

    PubMed  PubMed Central  Google Scholar 

  5. Yue Q, Zhang Y, Wang F, Cao F, Duan X, Bai J. Classification of colorectal carcinoma subtypes based on ferroptosis-associated molecular markers. World J Surg Oncol. 2022;20:117.

    PubMed  PubMed Central  Google Scholar 

  6. Lv Y, Feng QY, Zhang ZY, Zheng P, Zhu DX, Lin Q, et al. Low ferroptosis score predicts chemotherapy responsiveness and immune-activation in colorectal cancer. Cancer Med. 2023;12:2033–45.

    CAS  PubMed  Google Scholar 

  7. Liu Z, Zhao Q, Zuo ZX, Yuan SQ, Yu K, Zhang Q, et al. Systematic analysis of the aberrances and functional implications of ferroptosis in cancer. iScience. 2020;23:101302.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhai X, Lin Y, Zhu L, Wang Y, Zhang J, Liu J, et al. Ferroptosis in cancer immunity and immunotherapy: multifaceted interplay and clinical implications. Cytokine Growth Factor Rev. 2024;75:101–9.

    CAS  PubMed  Google Scholar 

  9. Wang W, Green M, Choi JE, Gijon M, Kennedy PD, Johnson JK, et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019;569:270–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Lin Z, Zou S, Wen K. The crosstalk of CD8+ T cells and ferroptosis in cancer. Front Immunol. 2023;14:1255443.

    CAS  PubMed  Google Scholar 

  11. Liao P, Wang W, Wang W, Kryczek I, Li X, Bian Y, et al. CD8(+) T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell. 2022;40:365–78. e366.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Bell HN, Stockwell BR, Zou W. Ironing out the role of ferroptosis in immunity. Immunity. 2024;57:941–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wu L, Sun S, Qu F, Liu X, Sun M, Pan Y, et al. ASCL2 affects the efficacy of immunotherapy in colon adenocarcinoma based on single-cell RNA sequencing analysis. Front Immunol. 2022;13:829640.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45:W98–W102.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Pelka K, Hofree M, Chen JH, Sarkizova S, Pirl JD, Jorgji V, et al. Spatially organized multicellular immune hubs in human colorectal cancer. Cell. 2021;184:4734–52 e4720.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Li T, Fu J, Zeng Z, Cohen D, Li J, Chen Q, et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 2020;48:W509–W514.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, et al. TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res. 2017;77:e108–e110.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013;39:782–95.

    CAS  PubMed  Google Scholar 

  19. Peng C, Tan Y, Yang P, Jin K, Zhang C, Peng W, et al. Circ-GALNT16 restrains colorectal cancer progression by enhancing the SUMOylation of hnRNPK. J Exp Clin Cancer Res. 2021;40:272.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Xiao S, Liu X, Yuan L, Chen X, Wang F. Expression of ferroptosis-related genes shapes tumor microenvironment and pharmacological profile in gastric cancer. Front Cell Dev Biol. 2021;9:694003.

    PubMed  PubMed Central  Google Scholar 

  21. Chen X, Comish PB, Tang D, Kang R. Characteristics and biomarkers of ferroptosis. Front Cell Dev Biol. 2021;9:637162.

    PubMed  PubMed Central  Google Scholar 

  22. Hao SH, Ma XD, Xu L, Xie JD, Feng ZH, Chen JW, et al. Dual specific phosphatase 4 suppresses ferroptosis and enhances sorafenib resistance in hepatocellular carcinoma. Drug Resist Updat. 2024;73:101052.

    CAS  PubMed  Google Scholar 

  23. Groschl B, Bettstetter M, Giedl C, Woenckhaus M, Edmonston T, Hofstadter F, et al. Expression of the MAP kinase phosphatase DUSP4 is associated with microsatellite instability in colorectal cancer (CRC) and causes increased cell proliferation. Int J Cancer. 2013;132:1537–46.

    PubMed  Google Scholar 

  24. Hijiya N, Tsukamoto Y, Nakada C, Tung Nguyen L, Kai T, Matsuura K, et al. Genomic loss of DUSP4 contributes to the progression of intraepithelial neoplasm of pancreas to invasive carcinoma. Cancer Res. 2016;76:2612–25.

    CAS  PubMed  Google Scholar 

  25. Raudsepp P, Bruggemann DA, Andersen ML. Detection of radicals in single droplets of oil-in-water emulsions with the lipophilic fluorescent probe BODIPY(665/676) and confocal laser scanning microscopy. Free Radic Biol Med. 2014;70:233–40.

    CAS  PubMed  Google Scholar 

  26. Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10:1523.

    PubMed  PubMed Central  Google Scholar 

  27. Kajarabille N, Latunde-Dada GO. Programmed cell-death by ferroptosis: antioxidants as mitigators. Int J Mol Sci. 2019;20:4968.

  28. O’Donnell KA, Yu D, Zeller KI, Kim JW, Racke F, Thomas-Tikhonenko A, et al. Activation of transferrin receptor 1 by c-Myc enhances cellular proliferation and tumorigenesis. Mol Cell Biol. 2006;26:2373–86.

    PubMed  PubMed Central  Google Scholar 

  29. Holland JP, Evans MJ, Rice SL, Wongvipat J, Sawyers CL, Lewis JS. Annotating MYC status with 89Zr-transferrin imaging. Nat Med. 2012;18:1586–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Ning B, Liu G, Liu Y, Su X, Anderson GJ, Zheng X, et al. 5-aza-2’-deoxycytidine activates iron uptake and heme biosynthesis by increasing c-Myc nuclear localization and binding to the E-boxes of transferrin receptor 1 (TfR1) and ferrochelatase (Fech) genes. J Biol Chem. 2011;286:37196–206.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Okazaki F, Matsunaga N, Okazaki H, Utoguchi N, Suzuki R, Maruyama K, et al. Circadian rhythm of transferrin receptor 1 gene expression controlled by c-Myc in colon cancer-bearing mice. Cancer Res. 2010;70:6238–46.

    CAS  PubMed  Google Scholar 

  32. Zheng Y, Sun L, Guo J, Ma J. The crosstalk between ferroptosis and anti-tumor immunity in the tumor microenvironment: molecular mechanisms and therapeutic controversy. Cancer Commun. 2023;43:1071–96.

    Google Scholar 

  33. Wang K, Coutifaris P, Brocks D, Wang G, Azar T, Solis S, et al. Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8(+) T cells. Cancer Cell. 2024;42:1582–1597 e1510.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Assouline B, Kahn R, Hodali L, Condiotti R, Engel Y, Elyada E, et al. Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8(+) T cell activation and limit responsiveness to immunotherapy in mice. Nat Commun. 2024;15:6162.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Yang S, Zhang D, Sun Q, Nie H, Zhang Y, Wang X, et al. Single-cell and spatial transcriptome profiling identifies the transcription factor BHLHE40 as a driver of EMT in metastatic colorectal cancer. Cancer Res. 2024;84:2202–17.

    CAS  PubMed  Google Scholar 

  36. Sim J, Yi K, Kim H, Ahn H, Chung Y, Rehman A, et al. Immunohistochemical expression of dual-specificity protein phosphatase 4 in patients with colorectal adenocarcinoma. Gastroenterol Res Pract. 2015;2015:283764.

    PubMed  PubMed Central  Google Scholar 

  37. Zhang H, Christensen CL, Dries R, Oser MG, Deng J, Diskin B, et al. CDK7 inhibition potentiates genome instability triggering anti-tumor immunity in small cell lung cancer. Cancer Cell. 2020;37:37–54 e39.

    CAS  PubMed  Google Scholar 

  38. Wang J, Zhang R, Lin Z, Zhang S, Chen Y, Tang J, et al. CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38alpha/MYC/PD-L1 signaling in non-small cell lung cancer. J Hematol Oncol. 2020;13:99.

    PubMed  PubMed Central  Google Scholar 

  39. Duster R, Anand K, Binder SC, Schmitz M, Gatterdam K, Fisher RP, et al. Structural basis of Cdk7 activation by dual T-loop phosphorylation. Nat Commun. 2024;15:6597.

    PubMed  PubMed Central  Google Scholar 

  40. Labbe JC, Martinez AM, Fesquet D, Capony JP, Darbon JM, Derancourt J, et al. p40MO15 associates with a p36 subunit and requires both nuclear translocation and Thr176 phosphorylation to generate cdk-activating kinase activity in Xenopus oocytes. EMBO J. 1994;13:5155–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Zinchuk V, Wu Y, Grossenbacher-Zinchuk O. Bridging the gap between qualitative and quantitative colocalization results in fluorescence microscopy studies. Sci Rep. 2013;3:1365.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Caunt CJ, Keyse SM. Dual-specificity MAP kinase phosphatases (MKPs): shaping the outcome of MAP kinase signalling. FEBS J. 2013;280:489–504.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Balko JM, Schwarz LJ, Bhola NE, Kurupi R, Owens P, Miller TW, et al. Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer. Cancer Res. 2013;73:6346–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Rottenberg S, Jonkers J. MEK inhibition as a strategy for targeting residual breast cancer cells with low DUSP4 expression. Breast Cancer Res. 2012;14:324.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Chitale D, Gong Y, Taylor BS, Broderick S, Brennan C, Somwar R, et al. An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors. Oncogene. 2009;28:2773–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Chen M, Zhang J, Berger AH, Diolombi MS, Ng C, Fung J, et al. Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis. J Clin Investig. 2019;129:215–22.

    PubMed  Google Scholar 

  47. Ichimanda M, Hijiya N, Tsukamoto Y, Uchida T, Nakada C, Akagi T, et al. Downregulation of dual-specificity phosphatase 4 enhances cell proliferation and invasiveness in colorectal carcinomas. Cancer Sci. 2018;109:250–8.

    CAS  PubMed  Google Scholar 

  48. Saigusa S, Inoue Y, Tanaka K, Toiyama Y, Okugawa Y, Shimura T, et al. Decreased expression of DUSP4 is associated with liver and lung metastases in colorectal cancer. Med Oncol. 2013;30:620.

    PubMed  Google Scholar 

  49. Schmid CA, Robinson MD, Scheifinger NA, Muller S, Cogliatti S, Tzankov A, et al. DUSP4 deficiency caused by promoter hypermethylation drives JNK signaling and tumor cell survival in diffuse large B cell lymphoma. J Exp Med. 2015;212:775–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. De Vriendt V, De Roock W, Di Narzo AF, Tian S, Biesmans B, Jacobs B, et al. DUSP 4 expression identifies a subset of colorectal cancer tumors that differ in MAPK activation, regardless of the genotype. Biomarkers. 2013;18:516–24.

    PubMed  Google Scholar 

  51. Remondini D, O’Connell B, Intrator N, Sedivy JM, Neretti N, Castellani GC, et al. Targeting c-Myc-activated genes with a correlation method: detection of global changes in large gene expression network dynamics. Proc Natl Acad Sci USA. 2005;102:6902–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Alvarez SW, Sviderskiy VO, Terzi EM, Papagiannakopoulos T, Moreira AL, Adams S, et al. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature. 2017;551:639–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Song J, Liu T, Yin Y, Zhao W, Lin Z, Yin Y, et al. The deubiquitinase OTUD1 enhances iron transport and potentiates host antitumor immunity. EMBO Rep. 2021;22:e51162.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Wang H, Jiao D, Feng D, Liu Q, Huang Y, Hou J, et al. Transformable supramolecular self-assembled peptides for cascade self-enhanced ferroptosis primed cancer immunotherapy. Adv Mater. 2024;36:e2311733.

    PubMed  Google Scholar 

  55. Xue Y, Lu F, Chang Z, Li J, Gao Y, Zhou J, et al. Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade. Nat Commun. 2023;14:4758.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Friedmann Angeli JP, Krysko DV, Conrad M. Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nat Rev Cancer. 2019;19:405–14.

    CAS  PubMed  Google Scholar 

  57. Dou J, Liu X, Yang L, Huang D, Tan X. Ferroptosis interaction with inflammatory microenvironments: Mechanism, biology, and treatment. Biomed Pharmacother. 2022;155:113711.

    CAS  PubMed  Google Scholar 

  58. Conche C, Finkelmeier F, Pesic M, Nicolas AM, Bottger TW, Kennel KB, et al. Combining ferroptosis induction with MDSC blockade renders primary tumours and metastases in liver sensitive to immune checkpoint blockade. Gut. 2023;72:1774–82.

    CAS  PubMed  Google Scholar 

  59. Li J, Liu J, Zhou Z, Wu R, Chen X, Yu C, et al. Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer. Sci Transl Med. 2023;15:eadg3049.

    CAS  PubMed  Google Scholar 

  60. Wang ST, Wang YY, Huang JR, Shu YB, He K, Shi Z. THZ2 ameliorates mouse colitis and colitis-associated colorectal cancer. Biomedicines 2024;12:679.

  61. Morita TY, Yu J, Kashima Y, Kamata R, Yamamoto G, Minamide T, et al. CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade. Nat Commun. 2023;14:7490.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Wein AN, McMaster SR, Takamura S, Dunbar PR, Cartwright EK, Hayward SL, et al. CXCR6 regulates localization of tissue-resident memory CD8 T cells to the airways. J Exp Med. 2019;216:2748–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Mabrouk N, Tran T, Sam I, Pourmir I, Gruel N, Granier C, et al. CXCR6 expressing T cells: functions and role in the control of tumors. Front Immunol. 2022;13:1022136.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Wang B, Wang Y, Sun X, Deng G, Huang W, Wu X, et al. CXCR6 is required for antitumor efficacy of intratumoral CD8(+) T cell. J Immunother Cancer. 2021,9:e003100.

  65. Di Pilato M, Kfuri-Rubens R, Pruessmann JN, Ozga AJ, Messemaker M, Cadilha BL, et al. CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment. Cell. 2021;184:4512–30. e4522.

    PubMed  PubMed Central  Google Scholar 

  66. Lv M, Gong Y, Liu X, Wang Y, Wu Q, Chen J, et al. CDK7-YAP-LDHD axis promotes D-lactate elimination and ferroptosis defense to support cancer stem cell-like properties. Signal Transduct Target Ther. 2023;8:302.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Li J, Dong T, Wu Z, Zhu D, Gu H. The effects of MYC on tumor immunity and immunotherapy. Cell Death Discov. 2023;9:103.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Guarducci C, Nardone A, Russo D, Nagy Z, Heraud C, Grinshpun A, et al. Selective CDK7 inhibition suppresses cell cycle progression and MYC signaling while enhancing apoptosis in therapy-resistant estrogen receptor-positive breast cancer. Clin Cancer Res. 2024;30:1889–905.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Zeng M, Kwiatkowski NP, Zhang T, Nabet B, Xu M, Liang Y, et al. Targeting MYC dependency in ovarian cancer through inhibition of CDK7 and CDK12/13. Elife. 2018,7:e39030.

Download references

Acknowledgements

We thank Dr Li Yang for pathological image analysis. We acknowledge the Core Facility of Jiangsu Provincial People’s Hospital for its help in the detection of experimental samples.

Funding

This study was supported by National Science Foundation of China (82273406) and the Jiangsu Province Capability Improvement Project through Science, Technology and Education (Jiangsu Provincial Medical Key Discipline, ZDXK202222).

Author information

Author notes

  1. These authors contributed equally: Dongsheng Zhang, Sheng Yang.

Authors and Affiliations

  1. Department of General Surgery, Colorectal Institute of Nanjing Medical University, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

    Dongsheng Zhang, Sheng Yang, Hengjie Xu, Zhihao Chen, Xiaowei Wang & Yueming Sun

  2. The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China

    Sheng Yang, Hengjie Xu, Zhihao Chen & Xiaowei Wang

  3. Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, Jiangsu, China

    Yueming Sun

  4. Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China

    Yueming Sun

  5. The Affiliated Shuyang Hospital of Xuzhou Medical University, Suqian, Jiangsu, China

    Yueming Sun

Authors
  1. Dongsheng Zhang
    View author publications

    Search author on:PubMed Google Scholar

  2. Sheng Yang
    View author publications

    Search author on:PubMed Google Scholar

  3. Hengjie Xu
    View author publications

    Search author on:PubMed Google Scholar

  4. Zhihao Chen
    View author publications

    Search author on:PubMed Google Scholar

  5. Xiaowei Wang
    View author publications

    Search author on:PubMed Google Scholar

  6. Yueming Sun
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Conception and design: DZ, SY, HX. Supervision: XW and YS. Development of methodology: DZ, SY, HX, and ZC. Acquisition of data: DZ, SY, HX, and ZC. Analysis and interpretation of data: DZ and SY. Writing, review and/or revision of the manuscript: DZ, SY, HX, XW, and YS.

Corresponding authors

Correspondence to Xiaowei Wang or Yueming Sun.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Approval from the Institutional Review Board of the First Affiliated Hospital of Nanjing Medical University (2022-SRFA-164) was obtained for human tissue study, and informed consent was provided by all patients involved. All animal experiments are conducted with the approval of the Committee on the Ethics of Animal Experiments of Nanjing Medical University (IACUC-2310067). All methods were performed in accordance with the relevant guidelines and regulations.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g., a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, D., Yang, S., Xu, H. et al. The novel role of DUSP4 in suppressing ferroptosis and promoting cytotoxicity of CD8+ T cells in MSI colorectal cancer. Br J Cancer 133, 1096–1110 (2025). https://doi.org/10.1038/s41416-025-03119-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41416-025-03119-w

Search

Advanced search

Quick links