1. An innovative NRF2 nano-modulator induces lung cancer ferroptosis and elicits an immunostimulatory tumor microenvironment.
- Author
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Hsieh CH, Hsieh HC, Shih FS, Wang PW, Yang LX, Shieh DB, and Wang YC
- Subjects
- AMP-Activated Protein Kinase Kinases, Allografts, Animals, Antineoplastic Agents pharmacology, CD8-Positive T-Lymphocytes immunology, Cell Line, Tumor, Cell Movement drug effects, Cell Movement immunology, Cell Survival drug effects, Cell Survival immunology, Chromatin Immunoprecipitation, Glycogen Synthase Kinase 3 metabolism, Humans, Iron chemistry, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Macrophages metabolism, Metal Nanoparticles administration & dosage, Metal Nanoparticles ultrastructure, Mice, Mice, Inbred BALB C, Mice, Nude, Mice, SCID, Microscopy, Electron, Transmission, Mitochondria drug effects, Mitochondria pathology, Mitochondria ultrastructure, NF-E2-Related Factor 2 genetics, Oxidative Stress drug effects, Protein Kinases, TOR Serine-Threonine Kinases metabolism, Tumor Microenvironment immunology, Ferroptosis drug effects, Iron pharmacology, Lung Neoplasms immunology, Lung Neoplasms metabolism, Macrophages drug effects, Metal Nanoparticles chemistry, NF-E2-Related Factor 2 metabolism, Tumor Microenvironment drug effects
- Abstract
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/β-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., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)- Published
- 2021
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