At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment
The evolutionary conserved DNA-sensing cGAS-STING innate immunity pathway represents one of the most important cytosolic DNA-sensing systems that is activated in response to viral invasion and/or damage to the integrity of the nuclear envelope. The key outcome of this pathway is the production of in...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-12-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/12/1675 |
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| author | Tatyana V. Korneenko Nikolay B. Pestov Ivan A. Nevzorov Alexandra A. Daks Kirill N. Trachuk Olga N. Solopova Nickolai A. Barlev |
| author_facet | Tatyana V. Korneenko Nikolay B. Pestov Ivan A. Nevzorov Alexandra A. Daks Kirill N. Trachuk Olga N. Solopova Nickolai A. Barlev |
| author_sort | Tatyana V. Korneenko |
| collection | DOAJ |
| description | The evolutionary conserved DNA-sensing cGAS-STING innate immunity pathway represents one of the most important cytosolic DNA-sensing systems that is activated in response to viral invasion and/or damage to the integrity of the nuclear envelope. The key outcome of this pathway is the production of interferon, which subsequently stimulates the transcription of hundreds of genes. In oncology, the situation is complex because this pathway may serve either anti- or pro-oncogenic roles, depending on context. The prevailing understanding is that when the innate immune response is activated by sensing cytosolic DNA, such as DNA released from ruptured micronuclei, it results in the production of interferon, which attracts cytotoxic cells to destroy tumors. However, in tumor cells that have adjusted to significant chromosomal instability, particularly in relapsed, treatment-resistant cancers, the cGAS–STING pathway often supports cancer progression, fostering the epithelial-to-mesenchymal transition (EMT). Here, we review this intricate pathway in terms of its association with cancer progression, giving special attention to pancreatic ductal adenocarcinoma and gliomas. As the development of new cGAS–STING-modulating small molecules and immunotherapies such as oncolytic viruses involves serious challenges, we highlight several recent fundamental discoveries, such as the proton-channeling function of STING. These discoveries may serve as guiding lights for potential pharmacological advancements. |
| first_indexed | 2024-03-08T20:27:07Z |
| format | Article |
| id | doaj.art-8eef0a70b5e841dcbe8118096edea3ba |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-08T20:27:07Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-8eef0a70b5e841dcbe8118096edea3ba2023-12-22T14:31:26ZengMDPI AGPharmaceuticals1424-82472023-12-011612167510.3390/ph16121675At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and TreatmentTatyana V. Korneenko0Nikolay B. Pestov1Ivan A. Nevzorov2Alexandra A. Daks3Kirill N. Trachuk4Olga N. Solopova5Nickolai A. Barlev6Group of Cross-Linking Enzymes, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, RussiaGroup of Cross-Linking Enzymes, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, RussiaInstitute of Cytology, Tikhoretsky ave 4, St-Petersburg 194064, RussiaInstitute of Cytology, Tikhoretsky ave 4, St-Petersburg 194064, RussiaChumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products, Moscow 108819, RussiaResearch Institute of Experimental Diagnostics and Tumor Therapy, Blokhin National Medical Research Center of Oncology, Moscow 115478, RussiaInstitute of Biomedical Chemistry, Moscow 119121, RussiaThe evolutionary conserved DNA-sensing cGAS-STING innate immunity pathway represents one of the most important cytosolic DNA-sensing systems that is activated in response to viral invasion and/or damage to the integrity of the nuclear envelope. The key outcome of this pathway is the production of interferon, which subsequently stimulates the transcription of hundreds of genes. In oncology, the situation is complex because this pathway may serve either anti- or pro-oncogenic roles, depending on context. The prevailing understanding is that when the innate immune response is activated by sensing cytosolic DNA, such as DNA released from ruptured micronuclei, it results in the production of interferon, which attracts cytotoxic cells to destroy tumors. However, in tumor cells that have adjusted to significant chromosomal instability, particularly in relapsed, treatment-resistant cancers, the cGAS–STING pathway often supports cancer progression, fostering the epithelial-to-mesenchymal transition (EMT). Here, we review this intricate pathway in terms of its association with cancer progression, giving special attention to pancreatic ductal adenocarcinoma and gliomas. As the development of new cGAS–STING-modulating small molecules and immunotherapies such as oncolytic viruses involves serious challenges, we highlight several recent fundamental discoveries, such as the proton-channeling function of STING. These discoveries may serve as guiding lights for potential pharmacological advancements.https://www.mdpi.com/1424-8247/16/12/1675STINGcGAScGAMPinterferon signalingcancermetastasis |
| spellingShingle | Tatyana V. Korneenko Nikolay B. Pestov Ivan A. Nevzorov Alexandra A. Daks Kirill N. Trachuk Olga N. Solopova Nickolai A. Barlev At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment Pharmaceuticals STING cGAS cGAMP interferon signaling cancer metastasis |
| title | At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment |
| title_full | At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment |
| title_fullStr | At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment |
| title_full_unstemmed | At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment |
| title_short | At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment |
| title_sort | at the crossroads of the cgas cgamp sting pathway and the dna damage response implications for cancer progression and treatment |
| topic | STING cGAS cGAMP interferon signaling cancer metastasis |
| url | https://www.mdpi.com/1424-8247/16/12/1675 |
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