Improved immunotherapy for gastric cancer by nanocomposites with capability of triggering Dual-Damage of Nuclear/Mitochondrial DNA and cGAS/STING-Mediated innate immunity
Improved immunotherapy for gastric cancer by nanocomposites with capability of triggering Dual-Damage of Nuclear/Mitochondrial DNA and cGAS/STING-Mediated innate immunity
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DOI：
10.1016/j.cej.2022.136428
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发表时间：
2022-04-21
影响因子：
15.1
通讯作者：
Hu, Yanfeng
中科院分区：
文献类型：
--
作者：
Guo, Weihong;Chen, Zhian;Hu, Yanfeng
基于免疫检查点抑制剂的癌症免疫疗法正在产生巨大的临床益处，但由于肿瘤微环境中缺乏T细胞浸润，其在胃癌（GC）中的疗效受到限制。值得注意的是，激活干扰素基因的DNA敏感性环GMP-AMP激酶-刺激因子（cGAS/STING）信号通路可以触发先天免疫和肿瘤浸润淋巴细胞的募集。本文中，我们将共负载的铂纳米颗粒（Pt-NPs;化学前药）和IR 820（光敏剂）构建到中空介孔有机二氧化硅纳米颗粒（称为HMON@IR 820/Pt-NPs）中。HMON@IR820/Pt-NP具有适当的尺寸分布，良好的生物相容性，并在温和的近红外辐射（0.7 W cm-2）下产生活性氧。重要的是，HMON@IR820/Pt-NP有效地进入GC细胞并释放负载的药物。Pt-NPs可以触发H2O2分解为O2，从而提高光动力学效率。此外，IR820还可进入线粒体，诱导线粒体氧化应激紊乱，导致线粒体DNA（mitoDNA）的释放。同时，这种氧化过程也允许Pt（0）氧化为具有细胞毒性的Pt（II），导致核DNA（nDNA）功能障碍。对nDNA和mitoDNA的双重损伤激活c-GAS/STING途径，刺激先天免疫，包括主要的抗肿瘤作用和CD8 + T细胞的募集，增强树突状细胞内的交叉呈递，并在远处肿瘤中维持致死性。总之，HMON@IR820/Pt-NP具有改善GC中免疫治疗功效的潜力。
Immune checkpoint inhibitors-based cancer immunotherapy is yielding great clinical benefit, but its efficacy is limited in gastric cancer (GC) by the lack of T-cell infiltration in the tumor microenvironment. Notably, activating the DNA-sensitive cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS/STING) signaling pathway could trigger innate immunity and recruitment of tumor-infiltrating lymphocytes. Herein, we constructed co-loaded platinum nanoparticles (Pt-NPs; chemo-prodrugs) and IR820 (photosensitizer) into hollow mesoporous organosilica nanoparticles (termed as HMON@IR820/Pt-NPs). The HMON@IR820/Pt-NPs exhibit appropriate size distribution, good biocompatibility, and generate reactive oxygen species under mild near infrared irradiation (0.7 W cm-2). Importantly, HMON@IR820/Pt-NPs efficiently enter GC cells and release loaded drugs. Pt-NPs can trigger H2O2 decomposition to O2, enhancing photodynamic efficiency. Furthermore, IR820 could enter into mitochondria, then induce mitochondria oxidative stress disorder, resulting in the releasing of oxidative mitochondrial DNA (mitoDNA). Meanwhile, this oxidative process also allowed for oxidation of Pt(0) to cytotoxic Pt(II), resulting in the dysfunction of nuclear DNA (nDNA). Dual-damage to nDNA and mitoDNA activates the c-GAS/STING pathway, stimulating innate immunity, including a primary anti-tumor effect and recruitment of CD8+ T cells, enhancing cross-presentation inside dendritic cells, and sustaining lethality in distant tumors. In summary, HMON@IR820/Pt-NPs have the potential to improve immunotherapy efficacy in GC.