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However, this immune\u2010enriched (IE) phenotype does not confer a significant survival advantage, highlighting the need to investigate its underlying mechanisms and identify effective therapies. By integrating in vitro drug screening and in silico sensitivity prediction, we identified the HDAC inhibitor vorinostat (SAHA) as a potent sensitizer to chemoimmunotherapy specifically in the IE\u2010PDAC. This effect was validated using T cell\u2010organoid co\u2010cultures and patient\u2010derived xenografts with humanized immune systems. Mechanistically, abundant cytokines (TNF\u2010\u03b1, FGF) in the IE tumor microenvironment promote FASN and PARP9 expression. This leads to free fatty acid accumulation and enhanced oxidative phosphorylation, supporting tumor cell survival. SAHA disrupts this \u201cmetabolic trap\u201d by concurrently suppressing FASN and PARP9. Single\u2010cell RNA sequencing revealed that the Gemcitabine\u2010SAHA combination remodels the tumor microenvironment by enhancing CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell function and depleting cancer\u2010associated fibroblasts. Clinically, we defined a CD8\n                    <jats:sup>high<\/jats:sup>\n                    \/FASN\n                    <jats:sup>high<\/jats:sup>\n                    \/PARP9\n                    <jats:sup>high<\/jats:sup>\n                    signature that identifies an IE patient subgroup with poor survival, representing those most likely to benefit from the \u201cGemcitabine\u2010Nivolumab\u2010SAHA\u201d triple\u2010combination therapy.\n                  <\/jats:p>","DOI":"10.1002\/advs.202521844","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T09:59:59Z","timestamp":1776074399000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Vorinostat Potentiates Chemoimmunotherapy in Immune\u2010Enriched Pancreatic Cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Chen","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pancreatic Surgery 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