Xu Guoshi, Shu Yinuo, Jiang Minhao, Zhang Yanjie, Zhu Jiawei, Peng Yinghua, Pu Fang, Ren Jinsong, Qu Xiaogang
State Key Laboratory of Rare Earth Resource Utilization and Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, P. R. China.
University of Science and Technology of China, Hefei, Anhui 230026, P. R. China.
Nano Lett. 2025 Jun 18;25(24):9834-9844. doi: 10.1021/acs.nanolett.5c02263. Epub 2025 Jun 6.
The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon gene (STING) pathway can respond to double-stranded DNA (dsDNA) to mediate innate immunity. However, activation of the cGAS/STING pathway initiates autophagy, which typically plays a negative regulatory role in the cGAS-STING pathway, largely attenuating the efficacy of antitumor immunity. Herein, we construct an oligonucleotide-based bioorthogonal platform to intervene in the crosstalk between the cGAS-STING pathway and autophagy, thereby achieving enhanced immunotherapy. In the platform, a dsDNA segment conjugated with unpaired guanosines serves as an agonist for the cGAS-STING pathway. The i-motif acts as a template for synthesizing palladium nanoparticles, which catalyze the synthesis of autophagy inhibitor and also function as carriers of oligonucleotides. Furthermore, the platform includes an aptamer for targeted delivery to cancer cells. In cancer cells, the platform activates the cGAS-STING pathway and disrupts autophagy, enhancing the anticancer immunity. This study provides a promising strategy to improve outcomes in tumor immunotherapy.
环磷酸鸟苷-腺苷合成酶（cGAS）/干扰素基因刺激因子（STING）通路可对双链DNA（dsDNA）作出反应，介导先天免疫。然而，cGAS/STING通路的激活会引发自噬，而自噬通常在cGAS-STING通路中发挥负性调节作用，在很大程度上削弱抗肿瘤免疫的功效。在此，我们构建了一个基于寡核苷酸的生物正交平台，以干预cGAS-STING通路与自噬之间的相互作用，从而实现增强免疫治疗。在该平台中，与未配对鸟苷缀合的dsDNA片段作为cGAS-STING通路的激动剂。i-基序作为合成钯纳米颗粒的模板，钯纳米颗粒催化自噬抑制剂的合成，并且还作为寡核苷酸的载体。此外，该平台包含一个用于靶向递送至癌细胞的适体。在癌细胞中，该平台激活cGAS-STING通路并破坏自噬，增强抗癌免疫力。本研究为改善肿瘤免疫治疗的疗效提供了一种有前景的策略。
