DNA derived from chemotherapeutics-killed tumor cells is one of the most important damage-associated molecular patterns that can activate the cGAS-STING (cyclic GMP-AMP synthase—stimulator of interferon genes) pathway in antigen-presenting cells (APCs) and promote antitumor immunity. However, conventional chemotherapy displays limited tumor cell killing and ineffective transfer of stable tumor DNA to APCs. Here we show that liposomes loaded with an optimized ratio of indocyanine green and doxorubicin, denoted as LID, efficiently generate reactive oxygen species upon exposure to ultrasound. LID plus ultrasound enhance the nuclear delivery of doxorubicin, induce tumor mitochondrial DNA oxidation, and promote oxidized tumor mitochondrial DNA transfer to APCs for effective activation of cGAS-STING signaling. Depleting tumor mitochondrial DNA or knocking out STING in APCs compromises the activation of APCs. Furthermore, systemic injection of LID plus ultrasound over the tumor lead to targeted cytotoxicity and STING activation, eliciting potent antitumor T cell immunity, which upon the combination with immune checkpoint blockade leads to regression of bilateral MC38, CT26, and orthotopic 4T1 tumors in female mice. Our study sheds light on the importance of oxidized tumor mitochondrial DNA in STING-mediated antitumor immunity and may inspire the development of more effective strategies for cancer immunotherapy.

来自化疗药物杀死的肿瘤细胞的 DNA 是最重要的损伤相关分子模式之一，可以激活抗原呈递细胞 (APC) 中的 cGAS-STING（环 GMP-AMP 合酶 - 干扰素基因刺激剂）途径并促进抗肿瘤免疫。然而，传统化疗对肿瘤细胞的杀伤有限，且无法有效地将稳定的肿瘤 DNA 转移至 APC。在这里，我们展示了装载有优化比例的吲哚菁绿和阿霉素（表示为 LID）的脂质体，在暴露于超声波时有效地产生活性氧。LID联合超声增强阿霉素的核递送，诱导肿瘤线粒体DNA氧化，并促进氧化的肿瘤线粒体DNA转移至APC，从而有效激活cGAS-STING信号传导。耗尽肿瘤线粒体 DNA 或敲除 APC 中的 STING 会损害 APC 的激活。此外，在肿瘤上全身注射 LID 加上超声可导致靶向细胞毒性和 STING 激活，引发有效的抗肿瘤 T 细胞免疫，与免疫检查点阻断相结合，可导致雌性小鼠双侧 MC38、CT26 和原位 4T1 肿瘤消退。我们的研究揭示了氧化的肿瘤线粒体 DNA 在 STING 介导的抗肿瘤免疫中的重要性，并可能激发开发更有效的癌症免疫治疗策略。