State Key Laboratory of Bio-Fibers and Eco-Textiles, Institute of Biochemical Engineering, The Affiliated Qingdao Central Hospital of Qingdao University, College of Materials Science and Engineering, Qingdao University, Qingdao 266071, China.
State Key Laboratory of Bio-Fibers and Eco-Textiles, Institute of Biochemical Engineering, The Affiliated Qingdao Central Hospital of Qingdao University, College of Materials Science and Engineering, Qingdao University, Qingdao 266071, China.
Acta Biomater. 2024 Feb;175:341-352. doi: 10.1016/j.actbio.2023.12.022. Epub 2023 Dec 18.
Cuproptosis is a recently identified copper-dependent form of nonapoptotic cell death and holds great prospect in cancer treatment. One of the most intriguing aspects of cuproptosis is its ability to synergize with apoptosis-based cancer treatments. Herein, we presented a novel approach using copper-coordinated nanoassemblies (CCNAs) that were constructed by incorporating a photosensitizer Zinc Phthalocyanine (ZnPc)-chemotherapeutic (DOX) prodrug with a thioketal (TK) spacer and an IDO inhibitor (1-methyl tryptophan, 1-MT) as building blocks for Cu-coordination self-assembly to achieve combinational apoptosis-cuproptosis and immunotherapy. Upon NIR laser irradiation, the ZnPc component of CCNAs exhibited a photodynamic effect that generated reactive oxygen species (ROS). This triggered the release of DOX, leading to enhanced tumor cell apoptosis. Additionally, the presence of Cu in the CCNAs not only enhanced the photodynamic process by catalyzing oxygen generation but also promoted the aggregation of toxic mitochondrial proteins, leading to cell cuproptosis. Importantly, the intensified cuproptosis-apoptosis effect triggered an immunogenic cell death (ICD) response. The released 1-MT complemented this response by reversing the immunosuppressive tumor microenvironment (ITM), synergistically amplifying anti-tumor immunity and suppressing the growth of primary and distant tumors. The findings of this study provide a new perspective on potential cancer treatments based on cuproptosis-apoptosis synergistic immunotherapy and stimulate further research in the design of advanced metal-coordinated nanomedicines. STATEMENT OF SIGNIFICANCE: The combination of cuproptosis and apoptosis that act with different mechanisms holds enormous potential in cancer treatment. Here, copper-coordinated nanoassemblies (CCNAs) based on photosensitizer-chemo prodrugs and checkpoint inhibitors were constructed for mediating cuproptosis-apoptosis and subsequently promoting cancer immunotherapy. CCNAs not only promoted the photodynamic effect and activation of chemotherapy through catalyzing the generation of oxygen but also induced toxic mitochondrial protein aggregation, leading to cell cuproptosis. These synergistic antitumor effects triggered robust immune responses with the aid of immune checkpoint blockade, almost eradicating primary tumors and inhibiting distant tumors by around 83 % without systemic toxicity.
铜死亡是一种新发现的依赖铜的非凋亡性细胞死亡形式，在癌症治疗中具有广阔的前景。铜死亡最有趣的方面之一是它能够与基于凋亡的癌症治疗协同作用。在此，我们提出了一种新的方法，使用铜配位纳米组装体（CCNAs），其构建方法是将光敏剂锌酞菁（ZnPc）-化疗药物（DOX）前药与硫代缩酮（TK）间隔物和 IDO 抑制剂（1-甲基色氨酸，1-MT）结合，用于 Cu 配位自组装，以实现联合凋亡-铜死亡和免疫治疗。在近红外激光照射下，CCNAs 的 ZnPc 组分表现出光动力效应，产生活性氧（ROS）。这触发了 DOX 的释放，导致肿瘤细胞凋亡增强。此外，CCNAs 中的 Cu 不仅通过催化氧气生成增强光动力过程，而且还促进有毒线粒体蛋白的聚集，导致细胞铜死亡。重要的是，强化的铜死亡-凋亡效应引发了免疫原性细胞死亡（ICD）反应。释放的 1-MT 通过逆转免疫抑制肿瘤微环境（ITM）来补充这种反应，协同放大抗肿瘤免疫并抑制原发性和远处肿瘤的生长。这项研究的结果为基于铜死亡-凋亡协同免疫治疗的潜在癌症治疗提供了新的视角，并激发了对先进金属配位纳米药物设计的进一步研究。意义声明：不同机制作用的铜死亡和凋亡的结合在癌症治疗中具有巨大的潜力。在这里，构建了基于光敏剂-化疗药物前体和检查点抑制剂的铜配位纳米组装体（CCNAs）来介导铜死亡-凋亡，进而促进癌症免疫治疗。CCNAs 不仅通过催化氧气生成促进光动力效应和化疗药物的激活，而且还诱导有毒的线粒体蛋白聚集，导致细胞铜死亡。这些协同的抗肿瘤效应在免疫检查点阻断的帮助下触发了强烈的免疫反应，几乎消除了原发性肿瘤，并抑制了 83%左右的远处肿瘤，而没有全身毒性。
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