Co-delivery of sorafenib and an FSP1 inhibitor triggers dual ferroptosis in tumor cells and immunosuppressive macrophages for enhanced immunotherapy in mouse models of hepatocellular carcinoma

  • Nat Commun. 2025 Nov 18;16(1):10096. doi: 10.1038/s41467-025-65056-9.
Chuanyu Tang  1  2  3  4  5  6 ,  Cheng He  1  2  3  4 ,  Decheng Wang  7 ,  Jie Guo  1  2  3  4 ,  Xiangyi Yin  1  2  3  4 ,  Hanjie Ye  1  2  3  4 ,  Lei Wu  8 ,  Yuling Zhang  5  6 ,  Silue Zeng  1  2  3  4  5  6 ,  Xiaojun Zeng  1  2  3  4 ,  Chengbo Liu  9  10 ,  Jingqin Chen  11  12 ,  Chihua Fang  13  14  15  16
Affiliations
  • 1. Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 2. Guangdong Provincial Clinical and Engineering Center of Digital Medicine, Guangzhou, China.
  • 3. National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments - South China Institute, Guangzhou, China.
  • 4. Digital Intelligent Minimally Invasive Surgery Institute, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 5. Research Center for Biomedical Optics and Molecular Imaging, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 6. State Key Laboratory of Biomedical Imaging Science and System, Shenzhen, China.
  • 7. Microbiome Medicine Center, Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 8. Department of Neurology, Guangdong Second Provincial General Hospital, Jinan University, Guangzhou, China.
  • 9. Research Center for Biomedical Optics and Molecular Imaging, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. [email protected].
  • 10. State Key Laboratory of Biomedical Imaging Science and System, Shenzhen, China. [email protected].
  • 11. Research Center for Biomedical Optics and Molecular Imaging, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. [email protected].
  • 12. State Key Laboratory of Biomedical Imaging Science and System, Shenzhen, China. [email protected].
  • 13. Department of Hepatobiliary Surgery I, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China. [email protected].
  • 14. Guangdong Provincial Clinical and Engineering Center of Digital Medicine, Guangzhou, China. [email protected].
  • 15. National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments - South China Institute, Guangzhou, China. [email protected].
  • 16. Digital Intelligent Minimally Invasive Surgery Institute, Zhujiang Hospital, Southern Medical University, Guangzhou, China. [email protected].
PMID: 41253833 DOI: 10.1038/s41467-025-65056-9
Abstract

The prevalence of immunosuppressive, tumor-associated macrophages (TAM) in the tumor microenvironment of hepatocellular carcinoma (HCC) compromises the efficacy of sorafenib (SF)-based, ferroptosis-inducing systemic therapies. Increasing the susceptibility of tumor cells and TAMs to Ferroptosis represents a promising breakthrough in improving the therapeutic outcomes of SF. Here, we show that the upregulation of Ferroptosis suppressor protein 1 (FSP1) counteracts SF-induced Ferroptosis independently of Glutathione Peroxidase 4 (GPX4) and correlates with increased immunosuppressive TAM infiltration and unfavorable prognosis. In preclinical HCC mouse models, biomimetic nanoparticles, co-loaded with SF and the FSP1 inhibitor viFSP1 and designed to simultaneously target tumor cells and immunosuppressive TAMs, enhance Ferroptosis in both cell types, promoting antigen presentation and cytotoxic T cell infiltration. Furthermore, combinatorial treatment with an anti-PD-L1 antibody suppresses metastasis and tumor recurrence. Thus, our nanoparticle-based dual-target strategy induces synergistic ferroptosis-immunotherapy in HCC, and represents a promising strategy to sensitize tumors to SF treatment, driving the remodeling of the immunosuppressive tumor microenvironment.

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