Cancer Immunotherapy Based on Cell Membrane-Coated Nanocomposites Augmenting cGAS/STING Activation by Efferocytosis Blockade
Cancer Immunotherapy Based on Cell Membrane-Coated Nanocomposites Augmenting cGAS/STING Activation by Efferocytosis Blockade
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DOI：
10.1002/smll.202302758
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发表时间：
2023-06-28
期刊：
影响因子：
13.3
通讯作者：
Hu, Yanfeng
中科院分区：
文献类型：
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作者：
Chen, Zhian;Li, Zhenhao;Hu, Yanfeng
由cGAS/STING途径触发的先天免疫具有改善癌症免疫疗法的潜力。此前，作者报道了死亡肿瘤细胞释放的双链DNA（dsDNA）可以触发cGAS/STING途径。然而，由于胞浆细胞增多症，垂死的肿瘤细胞在受损的dsDNA被释放之前被吞噬和清除;因此，发生免疫耐受和免疫逃逸。在本文中，通过增强cGAS/STING途径和抑制细胞增殖来合成表现出肿瘤免疫效应的癌细胞膜仿生纳米复合材料。一旦被癌细胞内化，就会触发联合化疗/化学动力学疗法，这会破坏它们的核和线粒体DNA。此外，释放的Annexin A5蛋白可抑制胞饮效应，并通过阻止磷脂酰丝氨酸暴露而促进免疫刺激性继发性坏死，导致dsDNA的爆发性释放。这些dsDNA片段作为免疫原性损伤的分子模式，从癌细胞中逃逸，激活cGAS/STING途径，增强树突状细胞内的交叉呈递，并促进肿瘤相关巨噬细胞的M1极化。体内实验表明，所提出的纳米复合材料可以招募细胞毒性T细胞，促进长期免疫记忆。此外，当与免疫检查点阻断相结合时，它可以增强免疫反应。因此，这种新型的仿生纳米复合物是一种很有前途的策略，产生适应性抗肿瘤免疫反应。
Innate immunity triggered by the cGAS/STING pathway has the potential to improve cancer immunotherapy. Previously, the authors reported that double-stranded DNA (dsDNA) released by dying tumor cells can trigger the cGAS/STING pathway. However, owing to efferocytosis, dying tumor cells are engulfed and cleared before the damaged dsDNA is released; hence, immunologic tolerance and immune escape occur. Herein, a cancer-cell-membrane biomimetic nanocomposites that exhibit tumor-immunotherapeutic effects are synthesized by augmenting the cGAS/STING pathway and suppressing efferocytosis. Once internalized by cancer cells, a combined chemo/chemodynamic therapy would be triggered, which damages their nuclear and mitochondrial DNA. Furthermore, the releasing Annexin A5 protein could inhibit efferocytosis effect and promote immunostimulatory secondary necrosis by preventing phosphatidylserine exposure, resulting in the burst release of dsDNA. These dsDNA fragments, as molecular patterns to immunogenic damage, escape from the cancer cells, activate the cGAS/STING pathway, enhance cross-presentation inside dendritic cells, and promote M1-polarization of tumor-associated macrophages. In vivo experiments suggest that the proposed nanocomposite could recruit cytotoxic T-cells and facilitate long-term immunological memory. Moreover, when combined with immune-checkpoint blockades, it could augment the immune response. Therefore, this novel biomimetic nanocomposite is a promising strategy for generating adaptive antitumor immune responses.