5-FU@HFn combined with decitabine induces pyroptosis and enhances antitumor immunotherapy for chronic myeloid leukemia
Abstract Background Tyrosine kinase inhibitors (TKIs) constitute the primary treatment for chronic myeloid leukemia (CML). However, resistance to TKIs often leads to treatment failure. Pyroptosis, a form of programmed cell death, has emerged as a promising strategy in cancer therapy due to its abili...
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BMC
2025-03-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-025-03335-9 |
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| author | Zuowei Yuan Guoyun Jiang Ying Yuan Qian Liang Yaxin Hou Wenyao Zhang Lujia Tang Kelong Fan Wenli Feng |
| author_facet | Zuowei Yuan Guoyun Jiang Ying Yuan Qian Liang Yaxin Hou Wenyao Zhang Lujia Tang Kelong Fan Wenli Feng |
| author_sort | Zuowei Yuan |
| collection | DOAJ |
| description | Abstract Background Tyrosine kinase inhibitors (TKIs) constitute the primary treatment for chronic myeloid leukemia (CML). However, resistance to TKIs often leads to treatment failure. Pyroptosis, a form of programmed cell death, has emerged as a promising strategy in cancer therapy due to its ability to eliminate tumor cells while stimulating antitumor immunity. Low-dose decitabine (DAC) has been shown to reverse methylation-induced silencing of the pyroptosis-related gene gasdermin E (GSDME) in some tumor cells, offering a potential new therapeutic option for CML. Herein, we propose a combination therapy using 5-fluorouracil (5-FU), a broad-spectrum chemotherapeutic agent, and low-dose DAC to induce pyroptosis in CML cells via the caspase-3/GSDME pathway. However, the nonspecific targeting of 5-FU diminishes its pyroptosis efficacy and causes off-target toxicity, highlighting the need for a targeted drug delivery system. Results In this study, we developed 5-FU@HFn nanoparticles (NPs) by loading 5-FU into the recombinant human heavy chain ferritin (HFn) nanocage through a high-temperature via the drug channels on the protein cage. The loading efficiency was approximately 50.62 ± 1.17 µg of 5-FU per mg of HFn. 5-FU@HFn NPs selectively targeted CML cells through CD71-mediated uptake, significantly enhancing the therapeutic effects of 5-FU. When combined with DAC, 5-FU@HFn NPs effectively activated pyroptosis via the caspase-3/GSDME pathway in both TKI-sensitive and TKI-resistant CML cells. In a CML mouse model, this combination therapy significantly suppressed tumorigenesis and triggered a robust antitumor immune response, facilitating the clearance of leukemic cells. Furthermore, the 5-FU@HFn NPs exhibited excellent in vivo safety. Conclusions The innovative therapeutic strategy, combining 5-FU@HFn nanoparticles with low-dose DAC, effectively induces caspase-3/GSDME-mediated pyroptosis and activates antitumor immunity for CML. This approach offers a potential alternative for patients resistant or intolerant to TKIs. Graphical abstract |
| format | Article |
| id | doaj-art-d10fbd0b085844bca23329bfe7742f60 |
| institution | DOAJ |
| issn | 1477-3155 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj-art-d10fbd0b085844bca23329bfe7742f602025-08-20T03:15:14ZengBMCJournal of Nanobiotechnology1477-31552025-03-0123111710.1186/s12951-025-03335-95-FU@HFn combined with decitabine induces pyroptosis and enhances antitumor immunotherapy for chronic myeloid leukemiaZuowei Yuan0Guoyun Jiang1Ying Yuan2Qian Liang3Yaxin Hou4Wenyao Zhang5Lujia Tang6Kelong Fan7Wenli Feng8Department of Clinical Hematology, School of Laboratory Medicine, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), Chongqing Medical UniversityDepartment of Clinical Hematology, School of Laboratory Medicine, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), Chongqing Medical UniversityDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical UniversityNanozyme Laboratory in Zhongyuan, Henan Academy of Innovations in Medical ScienceKey Laboratory of Biomacromolecules (CAS), CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS Engineering Laboratory for Nanozyme, Chinese Academy of SciencesDepartment of Clinical Hematology, School of Laboratory Medicine, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), Chongqing Medical UniversityDepartment of Clinical Hematology, School of Laboratory Medicine, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), Chongqing Medical UniversityNanozyme Laboratory in Zhongyuan, Henan Academy of Innovations in Medical ScienceDepartment of Clinical Hematology, School of Laboratory Medicine, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), Chongqing Medical UniversityAbstract Background Tyrosine kinase inhibitors (TKIs) constitute the primary treatment for chronic myeloid leukemia (CML). However, resistance to TKIs often leads to treatment failure. Pyroptosis, a form of programmed cell death, has emerged as a promising strategy in cancer therapy due to its ability to eliminate tumor cells while stimulating antitumor immunity. Low-dose decitabine (DAC) has been shown to reverse methylation-induced silencing of the pyroptosis-related gene gasdermin E (GSDME) in some tumor cells, offering a potential new therapeutic option for CML. Herein, we propose a combination therapy using 5-fluorouracil (5-FU), a broad-spectrum chemotherapeutic agent, and low-dose DAC to induce pyroptosis in CML cells via the caspase-3/GSDME pathway. However, the nonspecific targeting of 5-FU diminishes its pyroptosis efficacy and causes off-target toxicity, highlighting the need for a targeted drug delivery system. Results In this study, we developed 5-FU@HFn nanoparticles (NPs) by loading 5-FU into the recombinant human heavy chain ferritin (HFn) nanocage through a high-temperature via the drug channels on the protein cage. The loading efficiency was approximately 50.62 ± 1.17 µg of 5-FU per mg of HFn. 5-FU@HFn NPs selectively targeted CML cells through CD71-mediated uptake, significantly enhancing the therapeutic effects of 5-FU. When combined with DAC, 5-FU@HFn NPs effectively activated pyroptosis via the caspase-3/GSDME pathway in both TKI-sensitive and TKI-resistant CML cells. In a CML mouse model, this combination therapy significantly suppressed tumorigenesis and triggered a robust antitumor immune response, facilitating the clearance of leukemic cells. Furthermore, the 5-FU@HFn NPs exhibited excellent in vivo safety. Conclusions The innovative therapeutic strategy, combining 5-FU@HFn nanoparticles with low-dose DAC, effectively induces caspase-3/GSDME-mediated pyroptosis and activates antitumor immunity for CML. This approach offers a potential alternative for patients resistant or intolerant to TKIs. Graphical abstracthttps://doi.org/10.1186/s12951-025-03335-9Chronic myeloid leukemiaFerritin nanocage5-fluorouracilPyroptosisAntitumor immunity |
| spellingShingle | Zuowei Yuan Guoyun Jiang Ying Yuan Qian Liang Yaxin Hou Wenyao Zhang Lujia Tang Kelong Fan Wenli Feng 5-FU@HFn combined with decitabine induces pyroptosis and enhances antitumor immunotherapy for chronic myeloid leukemia Journal of Nanobiotechnology Chronic myeloid leukemia Ferritin nanocage 5-fluorouracil Pyroptosis Antitumor immunity |
| title | 5-FU@HFn combined with decitabine induces pyroptosis and enhances antitumor immunotherapy for chronic myeloid leukemia |
| title_full | 5-FU@HFn combined with decitabine induces pyroptosis and enhances antitumor immunotherapy for chronic myeloid leukemia |
| title_fullStr | 5-FU@HFn combined with decitabine induces pyroptosis and enhances antitumor immunotherapy for chronic myeloid leukemia |
| title_full_unstemmed | 5-FU@HFn combined with decitabine induces pyroptosis and enhances antitumor immunotherapy for chronic myeloid leukemia |
| title_short | 5-FU@HFn combined with decitabine induces pyroptosis and enhances antitumor immunotherapy for chronic myeloid leukemia |
| title_sort | 5 fu hfn combined with decitabine induces pyroptosis and enhances antitumor immunotherapy for chronic myeloid leukemia |
| topic | Chronic myeloid leukemia Ferritin nanocage 5-fluorouracil Pyroptosis Antitumor immunity |
| url | https://doi.org/10.1186/s12951-025-03335-9 |
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