An innovative NRF2 nano-modulator induces lung cancer ferroptosis and elicits an immunostimulatory tumor microenvironment.
An innovative NRF2 nano-modulator induces lung cancer ferroptosis and elicits an immunostimulatory tumor microenvironment.
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DOI：
10.7150/thno.57803
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发表时间：
2021
期刊：
影响因子：
12.4
通讯作者：
Wang YC
中科院分区：
文献类型：
--
作者：
Hsieh CH;Hsieh HC;Shih FS;Wang PW;Yang LX;Shieh DB;Wang YC
迄今为止，还没有报道过通过单一纳米药物同时靶向肿瘤微环境和癌细胞的情况。在这里，我们报告了零价铁纳米颗粒（ZVI-NP）诱导癌症特异性细胞毒性和抗癌免疫的双重性质。方法：采用MTT法检测ZVI-NP对肿瘤细胞的杀伤作用。使用线粒体功能测定、免疫荧光染色、Western印迹、RT-qPCR和ChIP-qPCR测定来剖析ZVI-NP诱导的铁凋亡癌细胞死亡的潜在机制。在免疫活性小鼠和人源化小鼠中评估ZVI-NP的治疗潜力。通过流式细胞术分析、RT-qPCR测定和免疫荧光检查同种异体移植物和离体培养的免疫细胞的免疫细胞谱。结果如下：ZVI-NP引起线粒体功能障碍、细胞内氧化应激和脂质过氧化，导致肺癌细胞的铁凋亡。在这种癌症特异性铁凋亡中，GSK 3/β-TrCP通过AMPK/mTOR活化对NRF 2的降解增强。此外，ZVI-NP减弱了癌症的自我更新能力并下调了血管生成相关基因。重要的是，ZVI-NP通过将促肿瘤M2巨噬细胞转移到抗肿瘤M1，减少调节性T细胞的数量，下调CD 8 + T细胞中的PD-1和CTLA 4以增强其对癌细胞的细胞溶解活性，同时在体外和荷瘤免疫活性小鼠中减弱癌细胞中的PD-L1表达，从而增强抗肿瘤免疫力。特别是，ZVI-NP优先在肿瘤和肺组织中积累，导致对肿瘤生长和转移的显著抑制。结论：这种双功能纳米药物建立了一种有效的策略，协同诱导铁蛋白癌细胞死亡和重组免疫抑制微环境，这突出了ZVI-NP作为一种先进的综合抗癌策略的潜力。
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.