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Epigenetic modifications play a critical role in PC progression, yet their contribution to chemoimmunotherapy resistance remains poorly understood. Here, we identified the transcription factor ZEB1 as a critical driver of chemoimmunotherapy resistance in PC.\n                    <jats:italic>ZEB1<\/jats:italic>\n                    knockdown synergized with gemcitabine and anti\u2013PD-1 therapy, markedly suppressed PC growth, and prolonged survival in vivo. Single-cell and spatial transcriptomics revealed that ZEB1 ablation promoted tumor pyroptosis by recruiting and activating GZMA\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in the tumor core through epigenetic upregulation of\n                    <jats:italic>CXCL16<\/jats:italic>\n                    . Meanwhile, ZEB1 blockade attenuates CD44\n                    <jats:sup>+<\/jats:sup>\n                    neutrophil\u2013induced CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell exhaustion by reducing tumor-derived SPP1 secretion, which otherwise promotes exhaustion through activation of the PD-L1\/PD-1 pathway. Clinically, high ZEB1 expression correlated with chemoresistance, immunosuppression, and diminished CXCL16 levels in patients with PC. Importantly, the epigenetic inhibitor mocetinostat (targeting ZEB1) potentiated the efficacy of chemoimmunotherapy, including anti\u2013PD-1 and CAR T therapies, in patient-derived organoids, xenografts, and orthotopic models. Our study unveils ZEB1 as a master epigenetic regulator of chemoimmunotherapy resistance and proposes its targeting as a transformative strategy for PC treatment.\n                  <\/jats:p>","DOI":"10.1172\/jci195970","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T16:00:24Z","timestamp":1757433624000},"source":"Crossref","is-referenced-by-count":14,"title":["ZEB1 promotes chemoimmunotherapy resistance in pancreatic cancer models by downregulating chromatin acetylation of CXCL16"],"prefix":"10.1172","volume":"135","author":[{"given":"Shaobo","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Molecular Oncology, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 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