Mesoporous manganese nanocarrier target delivery metformin for the co-activation STING pathway to overcome immunotherapy resistance
Yuanyao Dou,
Jie Zheng,
Jun Kang,
Liping Wang,
Daijuan Huang,
Yihui Liu,
Chao He,
Caiyu Lin,
Conghua Lu,
Di Wu,
Rui Han,
Li Li,
Liling Tang,
Yong He
Affiliations
Yuanyao Dou
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China; Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing 400042, China
Jie Zheng
Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing 400042, China; School of Medicine, Chongqing University, Chongqing 400044, China
Jun Kang
Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing 400042, China
Liping Wang
Department of pain treatment, the seventh people’s Hospital of Chongqing, Chongqing 401320, China
Daijuan Huang
Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing 400042, China; School of Medicine, Chongqing University, Chongqing 400044, China
Yihui Liu
Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing 400042, China
Chao He
Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing 400042, China
Caiyu Lin
Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing 400042, China
Conghua Lu
Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing 400042, China
Di Wu
Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing 400042, China
Rui Han
Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing 400042, China
Li Li
Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing 400042, China
Liling Tang
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China; Corresponding author
Yong He
Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing 400042, China; School of Medicine, Chongqing University, Chongqing 400044, China; Corresponding author
Summary: Targeting the stimulator of interferon genes (STING) pathway is a promising strategy to overcome primary resistance to immune checkpoint inhibitors in non-small cell lung cancer with the STK11 mutation. We previously found metformin enhances the STING pathway and thus promotes immune response. However, its low concentration in tumors limits its clinical use. Here, we constructed high-mesoporous Mn-based nanocarrier loading metformin nanoparticles (Mn-MSN@Met-M NPs) that actively target tumors and respond to release higher concentration of Mn2+ ions and metformin. The NPs significantly enhanced the T cells to kill lung cancer cells with the STK11 mutant. The mechanism shows that enhanced STING pathway activation promotes STING, TBKI, and IRF3 phosphorylation through Mn2+ ions and metformin release from NPs, thus boosting type I interferon production. In vivo, NPs in combination with a PD-1 inhibitor effectively decreased tumor growth. Collectively, we developed a Mn-MSN@Met-M nanoactivator to intensify immune activation for potential cancer immunotherapy.
