ZEB1 promotes chemoimmunotherapy resistance in pancreatic cancer models by downregulating chromatin acetylation of CXCL16
Shaobo Zhang, Yumeng Hu, Zhijun Zhou, Gaoyuan Lv, Chenze Zhang, Yuanyuan Guo, Fangxia Wang, Yuxin Ye, Haoran Qi, Hui Zhang, Wenming Wu, Min Li, Mingyang Liu
Shaobo Zhang, Yumeng Hu, Zhijun Zhou, Gaoyuan Lv, Chenze Zhang, Yuanyuan Guo, Fangxia Wang, Yuxin Ye, Haoran Qi, Hui Zhang, Wenming Wu, Min Li, Mingyang Liu
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Research Article Cell biology Oncology

ZEB1 promotes chemoimmunotherapy resistance in pancreatic cancer models by downregulating chromatin acetylation of CXCL16

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–PD-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+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 patients with PC. Importantly, the epigenetic inhibitor mocetinostat (targeting ZEB1) potentiated the efficacy of chemoimmunotherapy, including anti–PD-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.

Authors

Shaobo Zhang, Yumeng Hu, Zhijun Zhou, Gaoyuan Lv, Chenze Zhang, Yuanyuan Guo, Fangxia Wang, Yuxin Ye, Haoran Qi, Hui Zhang, Wenming Wu, Min Li, Mingyang Liu

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Figure 7

ZEB1 and CXCL16 are associated with chemotherapy resistance, immunosuppression, and prognosis in PC patients.

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ZEB1 and CXCL16 are associated with chemotherapy resistance, immunosuppr...
(A) Multiple immunofluorescence of ZEB1, CXCL16, and CD8 in tumor tissues of chemosensitive and chemoinsensitive PC patients. Scale bars: 50 μm. (B) Based on CXCL16 expression, tumor cells were categorized into CXCL16-high and CXCL16-low groups. (C) Compared with the chemoresistant group, tumor cells with high CXCL16 expression were predominantly found in the chemosensitive group. (D) Stacked histogram indicates a dramatic increase in the proportion of CD8+ T cells in the chemosensitive group. (E) In the TCGA dataset, patients receiving adjuvant gemcitabine chemotherapy were stratified into high-CXCL16-expression (n = 21) and low-expression groups (n = 44) based on the optimal cutoff value for CXCL16 gene expression. Kaplan-Meier survival curves indicate that patients with high CXCL16 expression exhibited a significantly better prognosis. (F) Schematic diagram. Crosstalk between PC cells, CD8+ T cells, and neutrophils contributes to tumor immune invasion and gemcitabine resistance through the ZEB1/HDAC1-CXCL16 signaling axis.