Abstract

Given the immense potential of sonodynamic therapy (SDT) in cancer treatment, designing effective sonosensitizers (SNSs) and elucidating their mechanisms are crucial for advancing the field and enhancing anti-tumor responses. However, there are still several limitations that hinder the application of SDT, such as the activation of the hypoxia-inducible factor-1 (HIF-1) pathway. Herein, we designed an endoplasmic reticulum (ER)-targeted iridium(III) SNS, C6IrAC, which exhibits specific toxicity towards tumor cells and excellent performance as a SNS. C6IrAC specifically targets the ER, causing ER stress, and under ultrasound (US) stimulation, the increased stress intensity enhances therapeutic efficacy. C6IrAC induces the degradation of HIF-1α and suppresses the HIF-1 pathway, thereby enhancing SDT. Furthermore, C6IrAC-induced ER stress leads to mitochondrial calcium overload, which subsequently results in the release of a large amount of mitochondrial DNA (mtDNA) into the cytoplasm, thereby activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Significant anti-tumor effects have been consistently observed both in vitro and in vivo. C6IrAC can effectively activate both the innate and adaptive immune systems, highlighting its substantial therapeutic potential. Taken together, this study provides a feasible method to overcome the limitations of SDT, and opens up new avenues for the design of SNSs.

文章链接：https://www.sciencedirect.com/science/article/pii/S1001841725003997?via%3Dihub#sec0002