Citation: Yubo Tan, Ziying Wang, Yibo An, Man Li, Dazhuang Xu, Renyuan Liu, Xinyu Tan, Yaohui He, Zhixiang Lu, Gang Liu. Molecular engineering organometallic sonosensitizer for enhanced sonodynamic therapy via promoting ER stress-mediated HIF-1α degradation and cGAS-STING pathway activation[J]. Chinese Chemical Letters, ;2026, 37(3): 111214. doi: 10.1016/j.cclet.2025.111214 shu

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

Yubo Tan ^{a, d, 1} ,
Ziying Wang ^{e, 1} ,
Yibo An ^{a, f, 1} ,
Man Li ^d ,
Dazhuang Xu ^b ,
Renyuan Liu ^a ,
Xinyu Tan ^d ,
Yaohui He ^{c, *,} ,
Zhixiang Lu ^{a, f, *,} ,
Gang Liu ^{b, *,}

a.
State Key Laboratory of Vaccines for Infectious Diseases & Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China
b.
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
c.
Institute for Future Sciences, University of South China, Changsha 410008, China
d.
School of Life Sciences, Xiamen University, Xiamen 361102, China
e.
Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China
f.
Sichuan Research Institute of Xiamen University, Chengdu 610000, China

2024001050@usc.edu.cn

zhixiangl@xmu.edu.cn

gangliu.cmitm@xmu.edu.cn

Received Date: 28 November 2024
Revised Date: 14 April 2025
Accepted Date: 15 April 2025
Available Online: 17 April 2025

Figures(5)

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.
- Sonodynamic therapy,
- Endoplasmic reticulum-stress,
- cGAS-STING,
- HIF-1α,
- Anti-tumor immunity
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