MiRNAs and the cGAS-STING Axis: Modulating Innate Immunity in Pathophysiological Contexts
Abstract
The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) signaling pathway is a central component of innate immunity that senses cytosolic double‑stranded DNA and initiates type I interferon and inflammatory responses. Controlled activation of this pathway is essential for antimicrobial defense and antitumor immune surveillance. In contrast, dysregulated or persistent signaling can promote chronic inflammation, tissue damage, autoimmune disorders, or immune evasion in cancer and infectious diseases. Therefore, tight regulation of cGAS–STING activity is critical for maintaining immune homeostasis. MicroRNAs (miRNAs) have emerged as key post‑transcriptional regulators that fine‑tune cGAS–STING signaling by directly targeting core pathway components or indirectly modulating related immune signaling molecules. This article provides a comprehensive review of current evidence describing miRNA‑mediated regulation of the cGAS–STING axis across diverse pathological contexts, including malignancies, viral and bacterial infections, and autoimmune or inflammatory diseases. In various cancers, miRNA‑mediated suppression of this pathway contributes to reduced interferon signaling, immune escape, therapy resistance, and tumor progression, although in certain cellular settings, controlled inhibition of cGAS–STING may exert protective or antitumor effects. During infectious diseases, some miRNAs are exploited by pathogens to attenuate innate immune sensing, whereas others enhance host defense by modulating negative regulators of immune signaling. In autoimmune and inflammatory disorders, dysregulated miRNA expression can either restrain excessive inflammation or exacerbate disease progression. Overall, this review underscores the miRNA–cGAS–STING regulatory axis as a dynamic and context‑specific network with broad relevance across human diseases.
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2. Hopfner KP, Hornung V. Molecular mechanisms and cellular functions of cGAS-STING signalling. Nat Rev Mol Cell Biol. 2020;21(9):501-21. https://doi.org/10.1038/s41580-020-0244-x.
3. Ritchie C, Carozza JA, Li L. Biochemistry, Cell Biology, and Pathophysiology of the Innate Immune cGAS-cGAMP-STING Pathway. Annu Rev Biochem. 2022;91(1):599-628. https://doi.org/10.1146/annurev-biochem-040320-101629.
4. Shah AU, Cao Y, Siddique N, Lin J, Yang Q. miR29a and miR378b Influence CpG-Stimulated Dendritic Cells and Regulate cGAS/STING Pathway. Vaccines (Basel). 2019;7(4):197. https://doi.org/10.3390/vaccines7040197.
5. Huang Z, Zhu J, Zhou YL, Shi J. The cGAS-STING pathway: a dual regulator of immune response in cancer and therapeutic implications. J Transl Med. 2025;23(1):766. https://doi.org/10.1186/s12967-025-06843-2.
6. Li Q, Wu P, Du Q, Hanif U, Hu H, Li K. cGAS–STING, an important signaling pathway in diseases and their therapy. MedComm. 2024;5(4):e511. https://doi.org/10.1002/mco2.511
7. Storozynsky Q, Hitt MM. The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer. Int J Mol Sci. 2020;21(22):8877. https://doi.org/10.3390/ijms21228877.
8. Guo J, Lu M, Wang C, Wang D, Ma T. Nucleic Acid Diversity in cGAS-STING Pathway Activation and Immune Dysregulation. Biomedicines. 2025;13(9):2158. https://doi.org/10.3390/biomedicines13092158.
9. Kato K, Omura H, Ishitani R, Nureki O. Cyclic GMP–AMP as an endogenous second messenger in innate immune signaling by cytosolic DNA. Annu Rev Biochem. 2017;86(1):541-66. https://doi.org/10.1146/annurev-biochem-061516-044813
10. Smith JA. STING, the endoplasmic reticulum, and mitochondria: is three a crowd or a conversation? Front Immunol. 2021;11:611347. https://doi.org/10.3389/fimmu.2020.611347
11. Yum S, Li M, Fang Y, Chen ZJ. TBK1 recruitment to STING activates both IRF3 and NF-κB that mediate immune defense against tumors and viral infections. Proc Natl Acad Sci. 2021;118(14):e2100225118. https://doi.org/10.1073/pnas.2100225118
12. Zhou R, Zhang Q, Xu P. TBK1, a central kinase in innate immune sensing of nucleic acids and beyond. Acta Biochim Biophys Sin (Shanghai). 2020;52(7):757-67. https://doi.org/10.1093/abbs/gmaa051.
13. Zhong S, Zhou Q, Yang J, Zhang Z, Zhang X, Liu J, et al. Relationship between the cGAS− STING and NF-κB pathways-role in neurotoxicity. Biomed Pharmacother 2024;175:116698. https://doi.org/10.1016/j.biopha.2024.116698
14. Wang Y, Zhu Y, Cao Y, Li Y, Zhang Z, Fleishman JS, et al. The activation of cGAS-STING pathway offers novel therapeutic opportunities in cancers. Front Immunol. 2025;16:1579832. https://doi.org/10.3389/fimmu.2025.1579832.
15. Cai G, Zhang X, Jiao J, Du W, Yan M. Targeting the cGAS-STING Pathway to Modulate Immune Inflammation in Diabetes and Cardiovascular Complications: Mechanisms and Therapeutic Insights. Curr Issues Mol Biol. 2025;47(9):750. https://doi.org/10.3390/cimb47090750.
16. Liang D, Xiao-Feng H, Guan-Jun D, Er-Ling H, Sheng C, Ting-Ting W, et al. Activated STING enhances Tregs infiltration in the HPV-related carcinogenesis of tongue squamous cells via the c-jun/CCL22 signal. Biochim Biophys Acta. 2015;1852(11):2494-503. https://doi.org/10.1016/j.bbadis.2015.08.011.
17. Bustos MA, Yokoe T, Shoji Y, Kobayashi Y, Mizuno S, Murakami T, et al. MiR-181a targets STING to drive PARP inhibitor resistance in BRCA- mutated triple-negative breast cancer and ovarian cancer. Cell Biosci. 2023;13(1):200. https://doi.org/10.1186/s13578-023-01151-y.
18. Knarr M, Avelar RA, Sekhar SC, Kwiatkowski LJ, Dziubinski ML, McAnulty J, et al. miR-181a initiates and perpetuates oncogenic transformation through the regulation of innate immune signaling. Nat Commun. 2020;11(1):3231. https://doi.org/10.1038/s41467-020-17030-w
19. Tankov S, Petrovic M, Lecoultre M, Espinoza F, El-Harane N, Bes V, et al. Hypoxic glioblastoma-cell-derived extracellular vesicles impair cGAS-STING activity in macrophages. Cell Commun Signal. 2024;22(1):144. https://doi.org/10.1186/s12964-024-01523-y.
20. Ren L, Guo D, Wan X, Qu R. EYA2 upregulates miR-93 to promote tumorigenesis of breast cancer by targeting and inhibiting the STING signaling pathway. Carcinogenesis. 2022;43(12):1121-30. https://doi.org/10.1093/carcin/bgab001
21. Wu MZ, Cheng WC, Chen SF, Nieh S, O'Connor C, Liu CL, et al. miR-25/93 mediates hypoxia-induced immunosuppression by repressing cGAS. Nat Cell Biol. 2017;19(10):1286-96. https://doi.org/10.1038/ncb3615.
22. Liu B, Lu K, Yuan L, Li X, Lan L, Han S. Hsa-miR-181a-2-3p inhibits the oncogenicity of colon cancer by directly targeting STING. Aging (Albany NY). 2024;16(15):11729-43. https://doi.org/10.18632/aging.206059.
23. Yu Q, Chu L, Li Y, Wang Q, Zhu J, Wang C, Cui S. miR-23a/b suppress cGAS-mediated innate and autoimmunity. Cell Mol Immunol. 2021;18(5):1235-48. https://doi.org/10.1038/s41423-021-00668-x.
24. Khan M, Harms JS, Liu Y, Eickhoff J, Tan JW, Hu T, et al. Brucella suppress STING expression via miR-24 to enhance infection. PLoS Pathog. 2020;16(10):e1009020. https://doi.org/10.1371/journal.ppat.1009020.
25. Sharma N, Wang C, Kessler P, Sen GC. Herpes simplex virus 1 evades cellular antiviral response by inducing microRNA-24, which attenuates STING synthesis. PLoS Pathog. 2021;17(9):e1009950. https://doi.org/10.1371/journal.ppat.1009950
26. Geddes VEV, de Oliveira AS, Tanuri A, Arruda E, Ribeiro-Alves M, Aguiar RS. MicroRNA and cellular targets profiling reveal miR-217 and miR-576-3p as proviral factors during Oropouche infection. PLoS Negl Trop Dis. 2018;12(5):e0006508. https://doi.org/10.1371/journal.pntd.0006508
27. Yarbrough ML, Zhang K, Sakthivel R, Forst CV, Posner BA, Barber GN, et al. Primate-specific miR-576-3p sets host defense signalling threshold. Nat Commun. 2014;5(1):4963. https://doi.org/10.1038/ncomms5963.
28. Xu T, Chu Q, Cui J. Rhabdovirus-Inducible MicroRNA-210 Modulates Antiviral Innate Immune Response via Targeting STING/MITA in Fish. J Immunol. 2018;201(3):982-94. https://doi.org/10.4049/jimmunol.1800377.
29. Yin D, Shao Y, Yang K, Tu J, Song X, Qi K, Pan X. Fowl adenovirus serotype 4 uses gga-miR-181a-5p expression to facilitate viral replication via targeting of STING. Vet Microbiol. 2021;263:109276. https://doi.org/10.1016/j.vetmic.2021.109276.
30. Zhang J, Li Z, Huang J, Yin H, Tian J, Qu L. miR-26a Inhibits Feline Herpesvirus 1 Replication by Targeting SOCS5 and Promoting Type I Interferon Signaling. Viruses. 2019;12(1):2. https://doi.org/10.3390/v12010002.
31. Song N, Song R, Ma P. MiR-340-5p alleviates neuroinflammation and neuronal injury via suppressing STING in subarachnoid hemorrhage. Brain Behav. 2022;12(9):e2687. https://doi.org/10.1002/brb3.2687.
32. He X-C, Wang J, Du H-Z, Liu C-M, Teng Z-Q. Intranasal administration of agomir-let-7i improves cognitive function in mice with traumatic brain injury. Cells. 2022;11(8):1348. https://doi.org/10.3390/cells11081348
33. Huang Z, Chen X, Yu B, Chen D. Cloning and functional characterization of rat stimulator of interferon genes (STING) regulated by miR-24. Dev Comp Immunol. 2012;37(3-4):414-20. https://doi.org/10.1016/j.dci.2012.02.010.
34. Shen A, Zheng D, Luo Y, Mou T, Chen Q, Huang Z, Wu Z. MicroRNA-24-3p alleviates hepatic ischemia and reperfusion injury in mice through the repression of STING signaling. Biochem Biophys Res Commun 2020;522(1):47-52. https://doi.org/10.1016/j.bbrc.2019.10.182
35. Tian X, Zhang P, Liu F, Yang L, Fu K, Gan K, Liu C. MicroRNA-4691-3p inhibits the inflammatory response by targeting STING in human dental pulp cells: A laboratory investigation. Int Endod J. 2023;56(11):1328-36. https://doi.org/10.1111/iej.13953.
36. Li N, Liu B, He R, Li G, Xiong R, Fu T, et al. HDAC3 promotes macrophage pyroptosis via regulating histone deacetylation in acute lung injury. iScience. 2023;26(7):107158. https://doi.org/10.1016/j.isci.2023.107158.
37. Albadawy R, Hasanin AH, Agwa SH, Hamady S, Mohamed RH, Gomaa E, et al. Prospective insight into the role of benzyl propylene glycoside as a modulator of the cGAS-STING signaling pathway in the management of nonalcoholic fatty pancreas animal model. Biol Res. 2023;56. https://doi.org/s40659-023-00423-8
2. Hopfner KP, Hornung V. Molecular mechanisms and cellular functions of cGAS-STING signalling. Nat Rev Mol Cell Biol. 2020;21(9):501-21. https://doi.org/10.1038/s41580-020-0244-x.
3. Ritchie C, Carozza JA, Li L. Biochemistry, Cell Biology, and Pathophysiology of the Innate Immune cGAS-cGAMP-STING Pathway. Annu Rev Biochem. 2022;91(1):599-628. https://doi.org/10.1146/annurev-biochem-040320-101629.
4. Shah AU, Cao Y, Siddique N, Lin J, Yang Q. miR29a and miR378b Influence CpG-Stimulated Dendritic Cells and Regulate cGAS/STING Pathway. Vaccines (Basel). 2019;7(4):197. https://doi.org/10.3390/vaccines7040197.
5. Huang Z, Zhu J, Zhou YL, Shi J. The cGAS-STING pathway: a dual regulator of immune response in cancer and therapeutic implications. J Transl Med. 2025;23(1):766. https://doi.org/10.1186/s12967-025-06843-2.
6. Li Q, Wu P, Du Q, Hanif U, Hu H, Li K. cGAS–STING, an important signaling pathway in diseases and their therapy. MedComm. 2024;5(4):e511. https://doi.org/10.1002/mco2.511
7. Storozynsky Q, Hitt MM. The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer. Int J Mol Sci. 2020;21(22):8877. https://doi.org/10.3390/ijms21228877.
8. Guo J, Lu M, Wang C, Wang D, Ma T. Nucleic Acid Diversity in cGAS-STING Pathway Activation and Immune Dysregulation. Biomedicines. 2025;13(9):2158. https://doi.org/10.3390/biomedicines13092158.
9. Kato K, Omura H, Ishitani R, Nureki O. Cyclic GMP–AMP as an endogenous second messenger in innate immune signaling by cytosolic DNA. Annu Rev Biochem. 2017;86(1):541-66. https://doi.org/10.1146/annurev-biochem-061516-044813
10. Smith JA. STING, the endoplasmic reticulum, and mitochondria: is three a crowd or a conversation? Front Immunol. 2021;11:611347. https://doi.org/10.3389/fimmu.2020.611347
11. Yum S, Li M, Fang Y, Chen ZJ. TBK1 recruitment to STING activates both IRF3 and NF-κB that mediate immune defense against tumors and viral infections. Proc Natl Acad Sci. 2021;118(14):e2100225118. https://doi.org/10.1073/pnas.2100225118
12. Zhou R, Zhang Q, Xu P. TBK1, a central kinase in innate immune sensing of nucleic acids and beyond. Acta Biochim Biophys Sin (Shanghai). 2020;52(7):757-67. https://doi.org/10.1093/abbs/gmaa051.
13. Zhong S, Zhou Q, Yang J, Zhang Z, Zhang X, Liu J, et al. Relationship between the cGAS− STING and NF-κB pathways-role in neurotoxicity. Biomed Pharmacother 2024;175:116698. https://doi.org/10.1016/j.biopha.2024.116698
14. Wang Y, Zhu Y, Cao Y, Li Y, Zhang Z, Fleishman JS, et al. The activation of cGAS-STING pathway offers novel therapeutic opportunities in cancers. Front Immunol. 2025;16:1579832. https://doi.org/10.3389/fimmu.2025.1579832.
15. Cai G, Zhang X, Jiao J, Du W, Yan M. Targeting the cGAS-STING Pathway to Modulate Immune Inflammation in Diabetes and Cardiovascular Complications: Mechanisms and Therapeutic Insights. Curr Issues Mol Biol. 2025;47(9):750. https://doi.org/10.3390/cimb47090750.
16. Liang D, Xiao-Feng H, Guan-Jun D, Er-Ling H, Sheng C, Ting-Ting W, et al. Activated STING enhances Tregs infiltration in the HPV-related carcinogenesis of tongue squamous cells via the c-jun/CCL22 signal. Biochim Biophys Acta. 2015;1852(11):2494-503. https://doi.org/10.1016/j.bbadis.2015.08.011.
17. Bustos MA, Yokoe T, Shoji Y, Kobayashi Y, Mizuno S, Murakami T, et al. MiR-181a targets STING to drive PARP inhibitor resistance in BRCA- mutated triple-negative breast cancer and ovarian cancer. Cell Biosci. 2023;13(1):200. https://doi.org/10.1186/s13578-023-01151-y.
18. Knarr M, Avelar RA, Sekhar SC, Kwiatkowski LJ, Dziubinski ML, McAnulty J, et al. miR-181a initiates and perpetuates oncogenic transformation through the regulation of innate immune signaling. Nat Commun. 2020;11(1):3231. https://doi.org/10.1038/s41467-020-17030-w
19. Tankov S, Petrovic M, Lecoultre M, Espinoza F, El-Harane N, Bes V, et al. Hypoxic glioblastoma-cell-derived extracellular vesicles impair cGAS-STING activity in macrophages. Cell Commun Signal. 2024;22(1):144. https://doi.org/10.1186/s12964-024-01523-y.
20. Ren L, Guo D, Wan X, Qu R. EYA2 upregulates miR-93 to promote tumorigenesis of breast cancer by targeting and inhibiting the STING signaling pathway. Carcinogenesis. 2022;43(12):1121-30. https://doi.org/10.1093/carcin/bgab001
21. Wu MZ, Cheng WC, Chen SF, Nieh S, O'Connor C, Liu CL, et al. miR-25/93 mediates hypoxia-induced immunosuppression by repressing cGAS. Nat Cell Biol. 2017;19(10):1286-96. https://doi.org/10.1038/ncb3615.
22. Liu B, Lu K, Yuan L, Li X, Lan L, Han S. Hsa-miR-181a-2-3p inhibits the oncogenicity of colon cancer by directly targeting STING. Aging (Albany NY). 2024;16(15):11729-43. https://doi.org/10.18632/aging.206059.
23. Yu Q, Chu L, Li Y, Wang Q, Zhu J, Wang C, Cui S. miR-23a/b suppress cGAS-mediated innate and autoimmunity. Cell Mol Immunol. 2021;18(5):1235-48. https://doi.org/10.1038/s41423-021-00668-x.
24. Khan M, Harms JS, Liu Y, Eickhoff J, Tan JW, Hu T, et al. Brucella suppress STING expression via miR-24 to enhance infection. PLoS Pathog. 2020;16(10):e1009020. https://doi.org/10.1371/journal.ppat.1009020.
25. Sharma N, Wang C, Kessler P, Sen GC. Herpes simplex virus 1 evades cellular antiviral response by inducing microRNA-24, which attenuates STING synthesis. PLoS Pathog. 2021;17(9):e1009950. https://doi.org/10.1371/journal.ppat.1009950
26. Geddes VEV, de Oliveira AS, Tanuri A, Arruda E, Ribeiro-Alves M, Aguiar RS. MicroRNA and cellular targets profiling reveal miR-217 and miR-576-3p as proviral factors during Oropouche infection. PLoS Negl Trop Dis. 2018;12(5):e0006508. https://doi.org/10.1371/journal.pntd.0006508
27. Yarbrough ML, Zhang K, Sakthivel R, Forst CV, Posner BA, Barber GN, et al. Primate-specific miR-576-3p sets host defense signalling threshold. Nat Commun. 2014;5(1):4963. https://doi.org/10.1038/ncomms5963.
28. Xu T, Chu Q, Cui J. Rhabdovirus-Inducible MicroRNA-210 Modulates Antiviral Innate Immune Response via Targeting STING/MITA in Fish. J Immunol. 2018;201(3):982-94. https://doi.org/10.4049/jimmunol.1800377.
29. Yin D, Shao Y, Yang K, Tu J, Song X, Qi K, Pan X. Fowl adenovirus serotype 4 uses gga-miR-181a-5p expression to facilitate viral replication via targeting of STING. Vet Microbiol. 2021;263:109276. https://doi.org/10.1016/j.vetmic.2021.109276.
30. Zhang J, Li Z, Huang J, Yin H, Tian J, Qu L. miR-26a Inhibits Feline Herpesvirus 1 Replication by Targeting SOCS5 and Promoting Type I Interferon Signaling. Viruses. 2019;12(1):2. https://doi.org/10.3390/v12010002.
31. Song N, Song R, Ma P. MiR-340-5p alleviates neuroinflammation and neuronal injury via suppressing STING in subarachnoid hemorrhage. Brain Behav. 2022;12(9):e2687. https://doi.org/10.1002/brb3.2687.
32. He X-C, Wang J, Du H-Z, Liu C-M, Teng Z-Q. Intranasal administration of agomir-let-7i improves cognitive function in mice with traumatic brain injury. Cells. 2022;11(8):1348. https://doi.org/10.3390/cells11081348
33. Huang Z, Chen X, Yu B, Chen D. Cloning and functional characterization of rat stimulator of interferon genes (STING) regulated by miR-24. Dev Comp Immunol. 2012;37(3-4):414-20. https://doi.org/10.1016/j.dci.2012.02.010.
34. Shen A, Zheng D, Luo Y, Mou T, Chen Q, Huang Z, Wu Z. MicroRNA-24-3p alleviates hepatic ischemia and reperfusion injury in mice through the repression of STING signaling. Biochem Biophys Res Commun 2020;522(1):47-52. https://doi.org/10.1016/j.bbrc.2019.10.182
35. Tian X, Zhang P, Liu F, Yang L, Fu K, Gan K, Liu C. MicroRNA-4691-3p inhibits the inflammatory response by targeting STING in human dental pulp cells: A laboratory investigation. Int Endod J. 2023;56(11):1328-36. https://doi.org/10.1111/iej.13953.
36. Li N, Liu B, He R, Li G, Xiong R, Fu T, et al. HDAC3 promotes macrophage pyroptosis via regulating histone deacetylation in acute lung injury. iScience. 2023;26(7):107158. https://doi.org/10.1016/j.isci.2023.107158.
37. Albadawy R, Hasanin AH, Agwa SH, Hamady S, Mohamed RH, Gomaa E, et al. Prospective insight into the role of benzyl propylene glycoside as a modulator of the cGAS-STING signaling pathway in the management of nonalcoholic fatty pancreas animal model. Biol Res. 2023;56. https://doi.org/s40659-023-00423-8
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| Issue | Vol 3 No 4 (2025) | |
| Section | Review Article(s) | |
| Keywords | ||
| cGAS–STING miRNAs cancer and infections autoimmune inflammatory diseases | ||
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How to Cite
1.
Amri J, Reza Zarei M, Esmaeilzadeh E, Meshkani R. MiRNAs and the cGAS-STING Axis: Modulating Innate Immunity in Pathophysiological Contexts. ABI. 2025;3(4):206-214.
