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Their oncogenic role depends on interaction with TEA domain (TEAD) transcription factors, making the TEAD-YAP\/TAZ complex a promising therapeutic target. Using translational mouse models, we show here that sustained systemic depletion of YAP and TAZ (YAP\/TAZ) caused severe side effects. These could be avoided through pulsed inhibition, which effectively suppressed tumor growth, even at advanced stages. We identified\n                    <jats:italic>Tgfb2<\/jats:italic>\n                    as a critical YAP\/TAZ target gene for tumor formation and demonstrated that YAP\/TAZ drove T cell exclusion via activation of tissue-remodeling genes. Consequently, YAP\/TAZ inhibition enhanced immune cell infiltration. However, infiltrating T cells rapidly underwent exhaustion. Combining YAP\/TAZ inhibition with immune checkpoint blockade reversed this exhaustion and sensitized resistant tumors to immunotherapy. This combination reshaped the tumor microenvironment to support immune cell infiltration and activation, representing a therapeutic strategy that maximizes antitumor immunity while minimizing toxicity.\n                  <\/jats:p>","DOI":"10.1172\/jci201579","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T16:02:56Z","timestamp":1783008176000},"source":"Crossref","is-referenced-by-count":1,"title":["Extracellular matrix reprogramming by the YAP\/TAZ\/TGF-\u03b22 axis drives immune exclusion in cholangiocarcinoma models"],"prefix":"10.1172","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5234-4786","authenticated-orcid":true,"given":"Marco","family":"Jessen","sequence":"first","affiliation":[{"name":"Transcriptional Control of Tissue Homeostasis Lab, Leibniz Institute on Aging, Fritz Lipmann Institute e.V. 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