{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T12:24:10Z","timestamp":1788265450523,"version":"build-2803163510"},"reference-count":38,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2024J011443"],"award-info":[{"award-number":["2024J011443"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172610"],"award-info":[{"award-number":["82172610"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The RAF\u2013MEK\u2013ERK pathway contributes to many human cancers, including intrahepatic cholangiocarcinoma (iCCA). Although MEK is an important therapeutic target, MEK inhibitors (MEKis) have limited efficacy as monotherapy in iCCA, and the underlying adaptive mechanisms remain unclear. Here, we show that MEK inhibition induces protective autophagy in iCCA cells. Mechanistically, MEK inhibition suppressed ERK\u2013RSK signaling, activated the LKB1\u2013ULK1 pathway, and promoted autophagy. MEK inhibition also increased reactive oxygen species (ROS) accumulation and activated PINK1\/Parkin\u2010mediated mitophagy. This autophagic response limited activation of the cGAS\u2013STING\u2013TBK1 pathway. Pharmacological or genetic inhibition of autophagy during MEK inhibition enhanced STING\u2010mediated type I interferon signaling, increased IFN\u2010\u03b1 and IFN\u2010\u03b2 expression, and sensitized iCCA cells to MEKi treatment. Consistently, combined MEK and autophagy inhibition suppressed tumor growth in xenograft\u2010bearing nude mice. These findings identify a link between MAPK signaling, autophagy, and innate immune sensing and support targeting the MEK\u2010autophagy\u2010STING axis to improve MEKi efficacy in iCCA.<\/jats:p>","DOI":"10.1111\/cas.70436","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T09:18:50Z","timestamp":1780391930000},"page":"2413-2425","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Combined MEK1\/2 and Autophagy Inhibition Suppresses Tumor Growth via STING\u2010Mediated Type I Interferon Response in iCCA"],"prefix":"10.1111","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2184-1899","authenticated-orcid":false,"given":"Chengqiang","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enfu","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangxia","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Intravenous Medicine Dispensing Weifang People's Hospital  Weifang 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Invasion (Ministry of Education), Zhongshan Hospital, Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1833-8988","authenticated-orcid":false,"given":"Yinghong","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiren","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ao","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion 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