癌症免疫治疗的疗效受限于“冷”肿瘤，其内在的免疫抑制肿瘤微环境 (TME) 导致患者反应率有限。激活干扰素基因刺激剂 (STING) 即使在“冷”肿瘤中也可提供有希望的抗肿瘤免疫，但 STING 激动剂的进一步推广受到了不良毒性、低特异性和缺乏可控性的阻碍。因此，在本文中，我们通过配位线粒体靶向配体三苯基膦 (TPP) 到声动力钴有机框架纳米片 (TPP@CoTCPP)，构建了一种超声可控的 cGAS-STING 增强型纳米刺激剂。只有通过声催化产生的 ROS 所引起的细胞质线粒体 DNA 泄漏被 cGAS 察觉到时，钴离子才会特异性地增强 STING 激活。在时空超声刺激下，局部 cGAS-STING 通路激活引起的一系列下游先天免疫炎症反应有效地激活抗肿瘤 T 细胞反应，针对典型免疫抑制性肿瘤进行骨转移瘤的治疗。我们还发现 TPP 的配位通过减小带隙、改善氧气吸附和增强电子转移，增强了 CoTCPP 纳米片的声动力效应。总体而言，我们的研究表明，在癌细胞中通过时空超声辐照控制的靶向和增强 cGAS-STING 激活可提高高效超声动力-离子免疫治疗对免疫抑制性肿瘤的治疗效果。版权所有 © 2023. 由 Elsevier Ltd.出版。

The therapeutic effect of cancer immunotherapy is restrained by limited patient response rate caused by 'cold' tumors with an intrinsically immunosuppressive tumor microenvironment (TME). Activating stimulator of interferon genes (STING) confers promising antitumor immunity even in 'cold' tumors, but the further promotion of STING agonists is hindered by undesirable toxicity, low specificity and lack of controllability. Herein, an ultrasound-controllable cGAS-STING amplifying nanoagonist was constructed by coordinating mitochondria-targeting ligand triphenylphosphonium (TPP) to sonodynamic cobalt organic framework nanosheets (TPP@CoTCPP). The Co ions specifically amplify STING activation only when cytosolic mitochondrial DNA leakage is caused by sonocatalysis-induced ROS production and sensed by cGAS. A series of downstream innate immune proinflammatory responses induced by local cGAS-STING pathway activation under spatiotemporal ultrasound stimulation efficiently prime the antitumor T-cell response against bone metastatic tumor, a typical immunosuppressive tumor. We also found that the coordination of TPP augments the sonodynamic effect of CoTCPP nanosheets by reducing the band gap, improving O2 adsorption and enhancing electron transfer. Overall, our study demonstrates that the targeted and amplified cGAS-STING activation in cancer cell controlled by spatiotemporal ultrasound irradiation boosts high-efficiency sonodynamic-ionicimmunotherapy against immunosuppressive tumor.Copyright © 2023. Published by Elsevier Ltd.