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Here, we demonstrate that Nsp15 limits antiviral innate immune responses in part by downregulating the cGAS\u2013STING pathway. To investigate how Nsp15 antagonizes host innate immune responses, we engineered recombinant SARS-CoV-2 bearing WT or EndoU-inactive Nsp15 (H234A). Compared with the WT virus, the Nsp15-H234A mutant exhibited a 2-log decrease in peak viral titres in interferon (IFN)-competent A549-ACE2 cells, but not in their STAT1 knockout counterparts. This attenuation was partially reversed by STING knockout or STING inhibitors, highlighting STING\u2019s involvement in Nsp15-driven immune evasion. Transcriptomic analyses revealed the upregulation of IFNs and IFN-stimulated genes in cells infected with the Nsp15-H234A mutant virus. Notably, cGAS and STING transcripts and proteins were suppressed during WT but not mutant virus infections \u2013 even in STAT1-deficient cells \u2013 suggesting that Nsp15 contributes directly to their downregulation.\n                    <jats:italic>In vitro<\/jats:italic>\n                    , Nsp15 targeted cGAS and STING transcripts in an EndoU activity-dependent manner, thereby reducing cGAS\u2013STING-driven IFN-\n                    <jats:italic>\u03b2<\/jats:italic>\n                    and NF-\n                    <jats:italic>\u03ba<\/jats:italic>\n                    B reporter activation. Infection of Syrian hamsters confirmed that the Nsp15-H234A mutant virus replicated to lower titres in respiratory tissues and elicited stronger expression of innate immune-related genes. Collectively, these findings define a key strategy by which SARS-CoV-2 Nsp15 subverts the cGAS\u2013STING pathway to facilitate viral replication and immune evasion and underscore Nsp15 EndoU activity as a potential target for future coronavirus antiviral or vaccine design.\n                  <\/jats:p>","DOI":"10.1099\/jgv.0.002233","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T17:16:21Z","timestamp":1774458981000},"source":"Crossref","is-referenced-by-count":2,"title":["SARS-CoV-2 Nsp15 facilitates immune evasion and viral replication by limiting multiple host innate immune pathways, including cGAS\u2013STING"],"prefix":"10.1099","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5010-7338","authenticated-orcid":false,"given":"Hsin-Ping","family":"Chiu","sequence":"first","affiliation":[{"name":"Department of Microbiology, Icahn School of Medicine, Mount Sinai, New York, NY, 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