Molecular engineering organometallic sonosensitizer for enhanced sonodynamic therapy via promoting ER stress-mediated HIF-1α degradation and cGAS-STING pathway activation

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, C 6 IrAC, which exhibits specific toxicity towards tumor cells and excellent performance as a SNS. C 6 IrAC specifically targets the ER, causing ER stress, and under ultrasound (US) stimulation, the increased stress intensity enhances therapeutic efficacy. C 6 IrAC induces the degradation of HIF-1α and suppresses the HIF-1 pathway, thereby enhancing SDT. Furthermore, C 6 IrAC-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 . C 6 IrAC 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. ER-targeted sonosensitizers, C6IrAC, induce ER stress, thereby activating the cGAS-STING pathway and inducing the degradation of HIF-1α. This approach overcomes the limitations of conventional sonosensitizers and reshapes the tumor immune microenvironment.