期刊
THERANOSTICS
卷 11, 期 14, 页码 7072-7091出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.57803
关键词
nanoparticle; NRF2; ferroptosis; tumor microenvironment; lung cancer
资金
- Taiwan Ministry of Science and Technology [MOST 108-2314-B-006-009-MY3, MOST 109-2320-B-006-032]
- National Health Research Institutes [NHRI-EX109-10726BI]
- National Applied Research Laboratories
This study demonstrates the dual properties of zero-valent-iron nanoparticles (ZVI-NP) in inducing cancer-specific cytotoxicity and anti-cancer immunity, highlighting their potential as an advanced integrated anti-cancer strategy. ZVI-NP not only induces cancer cell death but also enhances the anti-tumor immune response in animal models.
Simultaneous targeting of both the tumor microenvironment and cancer cells by a single nanomedicine has not been reported to date. Here, we report the dual properties of zero-valent-iron nanoparticle (ZVI-NP) to induce cancer-specific cytotoxicity and anti-cancer immunity. Methods: Cancer-specific cytotoxicity induced by ZVI-NP was determined by MTT assay. Mitochondria functional assay, immunofluorescence staining, Western blot, RT-qPCR, and ChIP-qPCR assays were used to dissect the mechanism underlying ZVI-NP-induced ferroptotic cancer cell death. The therapeutic potential of ZVI-NP was evaluated in immunocompetent mice and humanized mice. Immune cell profiles of allografts and ex vivo cultured immune cells were examined by flow cytometry analysis, RT-qPCR assay, and immunofluorescence. Results: ZVI-NP caused mitochondria dysfunction, intracellular oxidative stress, and lipid peroxidation, leading to ferroptotic death of lung cancer cells. Degradation of NRF2 by GSK3/beta-TrCP through AMPK/mTOR activation was enhanced in such cancer-specific ferroptosis. In addition, ZVI-NP attenuated self-renewal ability of cancer and downregulated angiogenesis-related genes. Importantly, ZVI-NP augmented anti-tumor immunity by shifting pro-tumor M2 macrophages to anti-tumor M1, decreasing the population of regulatory T cells, downregulating PD-1 and CTLA4 in CD8(+) T cells to potentiate their cytolytic activity against cancer cells, while attenuating PD-L1 expression in cancer cells in vitro and in tumor-bearing immunocompetent mice. In particular, ZVI-NPs preferentially accumulated in tumor and lung tissues, leading to prominent suppression of tumor growth and metastasis. Conclusions: This dual-functional nanomedicine established an effective strategy to synergistically induce ferroptotic cancer cell death and reprogram the immunosuppressive microenvironment, which highlights the potential of ZVI-NP as an advanced integrated anti-cancer strategy.
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