ZEB1 通过下调 CXCL16 染色质乙酰化促进胰腺癌模型中的化学免疫治疗耐药

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.