摘要
Pyroptosis is an inflammatory form of programmed cell death with great potential in cancer immunotherapies.Photodynamic therapy(PDT)represents a promising treatment modality to trigger pyroptosis.However,the hypoxic microenvironment inside the tumors often induces limited therapeutic efficacy.Herein,in this work,the first type of mitochondrial-targeting oxime-ester photogenerator(T-Oximer)was constructed to boost type-I ROS/aryl free radicals which could induce DNA damage by DNA cleaving and facilitate high-efficiency pyroptosis-mediated photoimmunotherapy.Detailed mechanism investigations revealed that T-Oximer could produce aryl free radicals via photolysis reaction and generate type-I ROS(O_(2)^(·-)and·OH)based on the type-I electron transfer process.Meanwhile,T-Oximer could accumulate in the mitochondria,boost mitochondrial radicals,and damage mitochondria in hypoxic tumor cells.Of peculiar interest,T-Oixmer could bind with DNA and cleave DNA to induce DNA damage.Combined mitochondrial damage with DNA cleavage,T-Oximer can initiate pyroptosis,activate the ICD effect,and trigger robust systemic antitumor immunity for efficient tumor regression and metastasis suppression.Our finding provides a new strategy for constructing oxygen-independent photogenerator for high-efficiency pyroptosis-mediated anti-hypoxia photoimmunotherapy.
基金
partially funded by the National Natural Science Foundation of China(No.22308192)
the Guangdong Provincial Special Support Program for Prominent Talents(2021JC06Y656)
the Natural Science Foundation of Guangdong Province,China(No.2023A1515012934)
Guangdong Province Marine Economic Development Project(No.GDNRC[2024]27).
作者简介
Qiyu Zhan,contributed equally to this work;Yulin Kuang,contributed equally to this work;Xuyuan Chen,contributed equally to this work;Yanzhen Yang,contributed equally to this work;Corresponding author:Shuoji Zhu,Guangdong Cardiovascular Institute,Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences),Southern Medical University,Guangzhou,Guangdong,510100,China.E-mail addresses:zhushuoji@gmail.com;Corresponding author:Huanlei Huang,Guangdong Cardiovascular Institute,Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences),Southern Medical University,Guangzhou,Guangdong,510100,China.E-mail addresses:huanghuanlei@gdph.org.cn;Corresponding author:Lei Wang,College of Materials and Chemical Engineering,Key Laboratory of Inorganic Nonmetallic Crystalline and Energy Conversion Materials,China Three Gorges University,Yichang,443002,China.E-mail addresses:lei.wang@ctgu.edu.cn;Corresponding author:Ping Zhu,Guangdong Cardiovascular Institute,Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences),Southern Medical University,Guangzhou,Guangdong,510100,China.E-mail addresses:tanganqier@163.com;Corresponding author:Ruiyuan Liu,Biomaterials Research Center,School of Biomedical Engineering,Southern Medical University,Guangzhou,510515,China.E-mail addresses:ruiyliu@smu.edu.cn。
