The cytosolic innate immune sensor cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is crucial for priming adaptive antitumour immunity through antigen-presenting cells (APCs). Natural agonists, such as cyclic dinucleotides (CDNs), activate the cGAS-STING pathway, but their clinical translation is impeded by poor cytosolic entry and serum stability, low specificity and rapid tissue clearance. Here we developed an ultrasound (US)-guided cancer immunotherapy platform using nanocomplexes composed of 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) electrostatically bound to biocompatible branched cationic biopolymers that are conjugated onto APC-targeting microbubbles (MBs). The nanocomplex-conjugated MBs engaged with APCs and efficiently delivered cGAMP into the cytosol via sonoporation, resulting in activation of cGAS-STING and downstream proinflammatory pathways that efficiently prime antigen-specific T cells. This bridging of innate and adaptive immunity inhibited tumour growth in both localized and metastatic murine cancer models. Our findings demonstrate that targeted local activation of STING in APCs under spatiotemporal US stimulation results in systemic antitumour immunity and improves the therapeutic efficacy of checkpoint blockade, thus paving the way towards novel image-guided strategies for targeted immunotherapy of cancer.

细胞溶质先天免疫传感器干扰素基因 (cGAS-STING) 通路的环状 GMP-AMP 合酶刺激物对于通过抗原呈递细胞 (APC) 启动适应性抗肿瘤免疫至关重要。天然激动剂，如环二核苷酸 (CDN)，可激活 cGAS-STING 通路，但它们的临床转化受到细胞溶质进入和血清稳定性差、特异性低和组织清除速度快的阻碍。在这里，我们开发了一种超声 (US) 引导的癌症免疫治疗平台，该平台使用由 2'3'-环磷酸鸟苷-磷酸腺苷 (cGAMP) 静电结合到生物相容性支链阳离子生物聚合物的纳米复合物，这些生物聚合物与 APC 靶向微泡 (MB) 结合。纳米复合物缀合的 MB 与 APC 结合，并通过声孔作用有效地将 cGAMP 递送到细胞质中，导致 cGAS-STING 和下游促炎通路的激活，从而有效启动抗原特异性 T 细胞。这种先天性和适应性免疫的桥接抑制了局部和转移性小鼠癌症模型中的肿瘤生长。我们的研究结果表明，在时空超声刺激下，APC 中 STING 的靶向局部激活会导致全身抗肿瘤免疫并提高检查点封锁的治疗效果，从而为癌症靶向免疫治疗的新型图像引导策略铺平道路。