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ResearchIn-Press PreviewCell biologyOncology Open Access | 10.1172/JCI195970

ZEB1 promotes chemo-immune resistance in pancreatic cancer models by downregulating chromatin acetylation of CXCL16

Shaobo Zhang,1 Yumeng Hu,1 Zhijun Zhou,2 Gaoyuan Lv,1 Chenze Zhang,3 Yuanyuan Guo,1 Fangxia Wang,1 Yuxin Ye,1 Haoran Qi,1 Hui Zhang,4 Wenming Wu,5 Min Li,2 and Mingyang Liu1

1State Key Laboratory of Molecular Oncology, National Cancer Center/National, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

2Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

3National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for M, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China

4Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

5Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Zhang, S. in: PubMed | Google Scholar

1State Key Laboratory of Molecular Oncology, National Cancer Center/National, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

2Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

3National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for M, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China

4Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

5Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Hu, Y. in: PubMed | Google Scholar

1State Key Laboratory of Molecular Oncology, National Cancer Center/National, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

2Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

3National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for M, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China

4Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

5Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Zhou, Z. in: PubMed | Google Scholar

1State Key Laboratory of Molecular Oncology, National Cancer Center/National, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

2Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

3National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for M, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China

4Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

5Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Lv, G. in: PubMed | Google Scholar

1State Key Laboratory of Molecular Oncology, National Cancer Center/National, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

2Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

3National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for M, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China

4Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

5Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Zhang, C. in: PubMed | Google Scholar

1State Key Laboratory of Molecular Oncology, National Cancer Center/National, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

2Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

3National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for M, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China

4Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

5Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Guo, Y. in: PubMed | Google Scholar

1State Key Laboratory of Molecular Oncology, National Cancer Center/National, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

2Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

3National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for M, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China

4Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

5Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Wang, F. in: PubMed | Google Scholar

1State Key Laboratory of Molecular Oncology, National Cancer Center/National, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

2Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

3National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for M, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China

4Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

5Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Ye, Y. in: PubMed | Google Scholar

1State Key Laboratory of Molecular Oncology, National Cancer Center/National, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

2Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

3National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for M, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China

4Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

5Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Qi, H. in: PubMed | Google Scholar

1State Key Laboratory of Molecular Oncology, National Cancer Center/National, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

2Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

3National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for M, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China

4Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

5Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Zhang, H. in: PubMed | Google Scholar

1State Key Laboratory of Molecular Oncology, National Cancer Center/National, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

2Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

3National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for M, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China

4Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

5Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Wu, W. in: PubMed | Google Scholar

1State Key Laboratory of Molecular Oncology, National Cancer Center/National, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

2Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

3National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for M, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China

4Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

5Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Li, M. in: PubMed | Google Scholar

1State Key Laboratory of Molecular Oncology, National Cancer Center/National, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

2Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America

3National Key Laboratory of Efficacy and Mechanism on Chinese Medicine for M, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China

4Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

5Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Find articles by Liu, M. in: PubMed | Google Scholar

Published September 9, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI195970.
Copyright © 2025, Zhang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 9, 2025 - Version history
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Abstract

Pancreatic cancer (PC) is notoriously resistant to both chemotherapy and immunotherapy, presenting a major therapeutic challenge. 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. ZEB1 knockdown synergized with gemcitabine and anti-PD1 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+CD8+ T cells in the tumor core through epigenetic upregulation of CXCL16. Meanwhile, ZEB1 blockade attenuates CD44+ neutrophil-induced CD8+ 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 PC patients. Importantly, the epigenetic inhibitor Mocetinostat (targeting ZEB1) potentiated chemoimmunotherapy efficacy, including anti-PD1 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.

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  • Version 1 (September 9, 2025): In-Press Preview
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