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However, the influence of YAP\/TAZ on cancer immune evasion remains poorly understood. Herein, we show that cancer patients harboring mutations regulating the Hippo pathway and YAP\/TAZ hyperactivation may be sensitized to immune checkpoint inhibitor (ICI) therapy owing to genome instability and\n                    <jats:italic>PD-L2<\/jats:italic>\n                    expression. LATS1\/2 deletion, accompanied by YAP\/TAZ hyperactivation, was associated with loss of squamous differentiation and genome instability, which may contribute to elevated DNA damage. Our data suggest that YAP\/TAZ may recruit TEAD, BRD4, and RNA polymerase \u2161 to the super-enhancer and promoter regions of\n                    <jats:italic>PD-L1<\/jats:italic>\n                    and\n                    <jats:italic>PD-L2<\/jats:italic>\n                    . YAP\/TAZ predominantly contribute to PD-L2 expression, which is associated with Stat3 activation, partially enhancing\n                    <jats:italic>PD-L1<\/jats:italic>\n                    transcription. YAP\/TAZ-activated cells can be targeted by antigen-specific T cells but evade them through PD-L2. These findings suggest that Hippo pathway alterations and associated YAP\/TAZ hyperactivation may serve as potential prognostic factors for stratifying patients undergoing ICI therapy. Targeting YAP\/TAZ\/TEAD could offer a promising treatment avenue for cancers harboring YAP\/TAZ hyperactivation.\n                  <\/jats:p>","DOI":"10.1038\/s42003-026-11092-0","type":"journal-article","created":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T09:01:25Z","timestamp":1792746085000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dysregulation of the Hippo pathway enhances PD-L2 transcription to promote immune evasion in head and neck squamous cell carcinoma"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3141-8173","authenticated-orcid":false,"given":"Toshinori","family":"Ando","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kento","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6014-1911","authenticated-orcid":false,"given":"Kuniaki","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7720-9740","authenticated-orcid":false,"given":"Yusuke","family":"Goto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Izumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanako","family":"Kataoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yume","family":"Ueda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukina","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Omachi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuga","family":"Maeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisako","family":"Furusho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramiro","family":"Iglesias-Bartolome","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Yoshimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0789-3273","authenticated-orcid":false,"given":"Tomoaki","family":"Shintani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Souichi","family":"Yanamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mutsumi","family":"Miyauchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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