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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2023
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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. |
format | Online Article Text |
id | pubmed-10306090 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
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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