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Activation of the cGAS-STING pathway by a mitochondrial DNA-targeted emissive rhodium(iii) metallointercalator

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (STING) pathway is a key mediator of innate immunity involved in cancer development and treatment. The roles of mitochondrial DNA (mtDNA) in cancer immunotherapy have gradually emerged. Herein, we report a highly emissive rhodium(iii) compl...

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Autores principales: Zheng, Yue, Chen, Xiao-Xiao, Zhang, Dong-Yang, Wang, Wen-Jin, Peng, Kun, Li, Zhi-Yuan, Mao, Zong-Wan, Tan, Cai-Ping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10306090/
https://www.ncbi.nlm.nih.gov/pubmed/37389261
http://dx.doi.org/10.1039/d3sc01737k
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author Zheng, Yue
Chen, Xiao-Xiao
Zhang, Dong-Yang
Wang, Wen-Jin
Peng, Kun
Li, Zhi-Yuan
Mao, Zong-Wan
Tan, Cai-Ping
author_facet Zheng, Yue
Chen, Xiao-Xiao
Zhang, Dong-Yang
Wang, Wen-Jin
Peng, Kun
Li, Zhi-Yuan
Mao, Zong-Wan
Tan, Cai-Ping
author_sort Zheng, Yue
collection PubMed
description The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (STING) pathway is a key mediator of innate immunity involved in cancer development and treatment. The roles of mitochondrial DNA (mtDNA) in cancer immunotherapy have gradually emerged. Herein, we report a highly emissive rhodium(iii) complex (Rh-Mito) as the mtDNA intercalator. Rh-Mito can specifically bind to mtDNA to cause the cytoplasmic release of mtDNA fragments to activate the cGAS-STING pathway. Moreover, Rh-Mito activates the mitochondrial retrograde signaling by disturbing the key metabolites involved in epigenetic modifications, which alters the nuclear genome methylation landscape to influence the expression of genes related to immune signaling pathways. Finally, we demonstrate that ferritin-encapsulated Rh-Mito elicits potent anticancer activities and evokes intense immune responses in vivo by intravenous injection. Overall, we report for the first time that small molecules targeting mtDNA can activate the cGAS-STING pathway, which gives insights into the development of biomacromolecule-targeted immunotherapeutic agents.
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spelling pubmed-103060902023-06-29 Activation of the cGAS-STING pathway by a mitochondrial DNA-targeted emissive rhodium(iii) metallointercalator Zheng, Yue Chen, Xiao-Xiao Zhang, Dong-Yang Wang, Wen-Jin Peng, Kun Li, Zhi-Yuan Mao, Zong-Wan Tan, Cai-Ping Chem Sci Chemistry The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (STING) pathway is a key mediator of innate immunity involved in cancer development and treatment. The roles of mitochondrial DNA (mtDNA) in cancer immunotherapy have gradually emerged. Herein, we report a highly emissive rhodium(iii) complex (Rh-Mito) as the mtDNA intercalator. Rh-Mito can specifically bind to mtDNA to cause the cytoplasmic release of mtDNA fragments to activate the cGAS-STING pathway. Moreover, Rh-Mito activates the mitochondrial retrograde signaling by disturbing the key metabolites involved in epigenetic modifications, which alters the nuclear genome methylation landscape to influence the expression of genes related to immune signaling pathways. Finally, we demonstrate that ferritin-encapsulated Rh-Mito elicits potent anticancer activities and evokes intense immune responses in vivo by intravenous injection. Overall, we report for the first time that small molecules targeting mtDNA can activate the cGAS-STING pathway, which gives insights into the development of biomacromolecule-targeted immunotherapeutic agents. The Royal Society of Chemistry 2023-06-06 /pmc/articles/PMC10306090/ /pubmed/37389261 http://dx.doi.org/10.1039/d3sc01737k Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Zheng, Yue
Chen, Xiao-Xiao
Zhang, Dong-Yang
Wang, Wen-Jin
Peng, Kun
Li, Zhi-Yuan
Mao, Zong-Wan
Tan, Cai-Ping
Activation of the cGAS-STING pathway by a mitochondrial DNA-targeted emissive rhodium(iii) metallointercalator
title Activation of the cGAS-STING pathway by a mitochondrial DNA-targeted emissive rhodium(iii) metallointercalator
title_full Activation of the cGAS-STING pathway by a mitochondrial DNA-targeted emissive rhodium(iii) metallointercalator
title_fullStr Activation of the cGAS-STING pathway by a mitochondrial DNA-targeted emissive rhodium(iii) metallointercalator
title_full_unstemmed Activation of the cGAS-STING pathway by a mitochondrial DNA-targeted emissive rhodium(iii) metallointercalator
title_short Activation of the cGAS-STING pathway by a mitochondrial DNA-targeted emissive rhodium(iii) metallointercalator
title_sort activation of the cgas-sting pathway by a mitochondrial dna-targeted emissive rhodium(iii) metallointercalator
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10306090/
https://www.ncbi.nlm.nih.gov/pubmed/37389261
http://dx.doi.org/10.1039/d3sc01737k
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