2. Academic Validation
  3. 5-FU@HFn combined with decitabine induces pyroptosis and enhances antitumor immunotherapy for chronic myeloid leukemia

5-FU@HFn combined with decitabine induces pyroptosis and enhances antitumor immunotherapy for chronic myeloid leukemia

  • J Nanobiotechnology. 2025 Mar 28;23(1):252. doi: 10.1186/s12951-025-03335-9.
Zuowei Yuan # 1 2,  Guoyun Jiang # 1 3,  Ying Yuan # 4,  Qian Liang 5,  Yaxin Hou 6,  Wenyao Zhang 1,  Lujia Tang 1,  Kelong Fan 7 8,  Wenli Feng 9
Affiliations

Affiliations

  • 1 Department of Clinical Hematology, School of Laboratory Medicine, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China.
  • 2 Department of Clinical Laboratory, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China.
  • 3 Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
  • 4 Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 5 Nanozyme Laboratory in Zhongyuan, Henan Academy of Innovations in Medical Science, Zhengzhou, Henan, 451163, China.
  • 6 Key Laboratory of Biomacromolecules (CAS), CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS Engineering Laboratory for Nanozyme, Chinese Academy of Sciences, Beijing, 100101, China.
  • 7 Nanozyme Laboratory in Zhongyuan, Henan Academy of Innovations in Medical Science, Zhengzhou, Henan, 451163, China. fankelong@ibp.ac.cn.
  • 8 Key Laboratory of Biomacromolecules (CAS), CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, CAS Engineering Laboratory for Nanozyme, Chinese Academy of Sciences, Beijing, 100101, China. fankelong@ibp.ac.cn.
  • 9 Department of Clinical Hematology, School of Laboratory Medicine, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China. fengwl@cqmu.edu.cn.
  • # Contributed equally.
PMID: 40148810 DOI: 10.1186/s12951-025-03335-9
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.

Keywords

5-fluorouracil; Antitumor immunity; Chronic myeloid leukemia; Ferritin nanocage; Pyroptosis.

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