在我们之前的研究中，我们首次发现替莫唑胺（TMZ），一种胶质母细胞瘤（GBM）的一线化疗药物，在超声波辐照下能够产生大量活性氧自由基（ROS）。以TMZ为声敏感剂的声动力治疗（SDT），比单独应用TMZ具有更强的抗肿瘤效果。在这里，我们进一步评估了基于TMZ的SDT对亚细胞结构的影响，并探讨了基于TMZ的SDT诱导的免疫原性细胞死亡（ICD）能力。我们使用LN229和GL261胶质瘤细胞探究了TMZ的声毒性效应。通过透射电子显微镜观察内质网和线粒体的形态。γ-H2AX染色表示核DNA损伤。我们使用骨髓源性树突状细胞（BMDCs）评估了基于TMZ的SDT的ICD诱导能力。我们使用循环精氨酸-甘氨酸-天冬氨酸（c(RGDyC)）修饰的纳米脂质体药物传递平台来改善SDT的肿瘤靶向性。基于TMZ的SDT对胶质瘤细胞具有更强的抑制作用。透射电子显微镜显示TMZ基于SDT引起内质网扩张和线粒体肿胀。此外，TMZ基于SDT还促进内质网应激反应（ERSR），核DNA损伤和线粒体通透性转换孔（mPTP）的开放。最重要的是，我们发现TMZ基于SDT可以促进胶质瘤细胞产生的“危险信号”，诱导BMDCs的成熟和激活，这与胶质瘤细胞释放的线粒体DNA进入细胞质有关。体内实验证明，TMZ基于SDT可以重新塑造胶质瘤免疫微环境，并引发持久而强大的抗肿瘤免疫应答。此外，TMZ的工程纳米脂质体载体赋予了SDT的肿瘤靶向性，为未来TMZ与SDT联合治疗的安全临床应用提供了选项。基于TMZ的SDT能够触发胶质瘤的ICD。TMZ作为声敏感剂的发现在GBM的治疗中显示出了巨大的前景。版权所有©2023。由Elsevier Inc.出版。

In our previous study, we found for the first time that temozolomide (TMZ), the first-line chemotherapeutic agent for glioblastoma (GBM), can generate a large amount of reactive oxygen species (ROS) under ultrasound irradiation. Sonodynamic therapy (SDT) using TMZ as the sonosensitizer produced more potent antitumor effects than TMZ alone. Here, we further evaluate the effects of TMZ-based SDT on subcellular structures and investigate the immunogenic cell death (ICD)-inducing capability of TMZ-based SDT.The sonotoxic effects of TMZ were explored in LN229 and GL261 glioma cells. The morphology of endoplasmic reticulum and mitochondria was observed by transmission electron microscopy. The nuclear DNA damage was represented by γ-H2AX staining. Bone marrow-derived dendritic cells (BMDCs) were employed to assess ICD-inducing capability of TMZ-based SDT. A cyclic arginine-glycine-aspartic (c(RGDyC))-modified nanoliposome drug delivery platform was used to improve the tumor targeting of SDT.TMZ-based SDT had a greater inhibitory effect on glioma cells than TMZ alone. Transmission electron microscopy revealed that TMZ-based SDT caused endoplasmic reticulum dilation and mitochondrial swelling. In addition, endoplasmic reticulum stress response (ERSR), nuclear DNA damage and mitochondrial permeability transition pore (mPTP) opening were promoted in TMZ-based SDT group. Most importantly, we found that TMZ-based SDT could promote the "danger signals" produced by glioma cells and induce the maturation and activation of BMDCs, which was associated with the mitochondrial DNA released into the cytoplasm in glioma cells. In vivo experiments showed that TMZ-based SDT could remodel glioma immune microenvironment and provoke durable and powerful anti-tumor immune responses. What's more, the engineered nanoliposome vector of TMZ conferred SDT tumor targeting, providing an option for safer clinical application of TMZ in combination with SDT in the future.TMZ-based SDT was capable of triggering ICD in glioma. The discovery of TMZ as a sonosensitizer have shown great promise in the treatment of GBM.Copyright © 2023. Published by Elsevier Inc.