{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T18:20:06Z","timestamp":1771438806837,"version":"3.50.1"},"reference-count":0,"publisher":"Cold Spring Harbor Laboratory","funder":[{"name":"Eleanor and Miles Shore Faculty Development Awards Program"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35 CA210057"],"award-info":[{"award-number":["R35 CA210057"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R35 CA231945"],"award-info":[{"award-number":["R35 CA231945"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes Dev."],"accepted":{"date-parts":[[2025,12,1]]},"abstract":"<jats:p>Loss of the tumor suppressor PTEN is strongly associated with a lack of response to immune checkpoint blockade therapies in cancer patients, but the underlying mechanisms are not fully understood. We have developed a transformation model where knocking out PTEN in human mammary epithelial cells drives dependence on the p110\u03b2 subunit of PI3K and, notably, elicits a robust induction of endogenous retroviral elements (ERVs) and activation of interferon signaling. This constitutive cell-intrinsic interferon response, hallmarked by hyperactivated STAT1, is also observed in human tumors with a PTEN-low status. We further found that PTEN deficiency renders cancer cells resistant to the cytotoxic effects of immune cells and interferon-\u03b3. Notably, PTEN loss also results in a dependency on an activated DNA damage response pathway, leading to an exquisite vulnerability to CDK12 inhibition. Our study suggests an interferon adaptation model in which tumors driven by PTEN deficiency inherently activate the interferon response, enabling them to adapt to interferon cytotoxicity and gain resistance to immunotherapies.<\/jats:p>","DOI":"10.1101\/gad.353283.125","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T17:55:10Z","timestamp":1771437310000},"source":"Crossref","is-referenced-by-count":0,"title":["Loss of the tumor suppressor PTEN activates cell-intrinsic interferon signaling to drive immune resistance"],"prefix":"10.1101","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2703-3104","authenticated-orcid":false,"given":"Yubao","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1067-883X","authenticated-orcid":false,"given":"Cherubin","family":"Manokaran","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5205-9923","authenticated-orcid":false,"given":"Yutian","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5378-6284","authenticated-orcid":false,"given":"Jiajia","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;"},{"name":"Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0204-2875","authenticated-orcid":false,"given":"Hao","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0346-5033","authenticated-orcid":false,"given":"David","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;"},{"name":"Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6362-561X","authenticated-orcid":false,"given":"Philippe","family":"Bousso","sequence":"additional","affiliation":[{"name":"Dynamics of Immune Responses Unit, U1223, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Institut Pasteur, Universit\u00e9 de Paris Cit\u00e9 Paris 75015, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4561-5688","authenticated-orcid":false,"given":"Jean J.","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA;"},{"name":"Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6453-3955","authenticated-orcid":false,"given":"Thomas M.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"246","published-online":{"date-parts":[[2026,2,18]]},"container-title":["Genes &amp; Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/gad.353283.125","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T17:55:11Z","timestamp":1771437311000},"score":1,"resource":{"primary":{"URL":"http:\/\/genesdev.cshlp.org\/lookup\/doi\/10.1101\/gad.353283.125"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,18]]},"references-count":0,"alternative-id":["10.1101\/gad.353283.125"],"URL":"https:\/\/doi.org\/10.1101\/gad.353283.125","relation":{},"ISSN":["0890-9369","1549-5477"],"issn-type":[{"value":"0890-9369","type":"print"},{"value":"1549-5477","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,18]]}}}