胰腺导管腺癌（PDAC）由于其固有的肿瘤异质性、难治性癌干/启动细胞存活以及免疫抑制性肿瘤微环境（TME）中的免疫逃逸，致使其对目前的治疗方法具有抵抗性。本研究结果显示，临床PDAC和邻近组织经历了不同的染色质重塑。多重组学分析揭示了与H3K4me3谱系相似的致癌基因DEAD-box RNA helicase 18（DDX18）的上调表达，并与PDAC患者的不良生存相关。我们验证了DDX18在STAT1启动子区域上的沉积，并通过调节PRC2复合物的形成来拮抗STAT1启动子序列上的H3K27me3沉积，从而上调STAT1的表达。这导致PD-L1表达的上调、T淋巴细胞的聚集和过度激活，以及高度成瘤性和免疫抑制性胰腺TME的形成。DDX18-STAT1轴抑制还同时影响到癌细胞的干细胞特性、上皮-间质转化（EMT）以及免疫抑制性TME的破坏，通过与抗-PD-L1疗法协同作用，可产生对侵袭性PDAC的持续缓解。将DDX18抑制与抗-PD-L1免疫化疗相结合，用于治疗PDAC患者将为PDAC患者的临床治疗开辟一条新途径。本研究发现临床PDAC和邻近胰腺组织经历了特定的染色质重塑，其特点之一就是DEAD-box RNA helicase 18（DDX18）的上调表达。我们进一步验证了DDX18在STAT1启动子区域上的沉积，并通过调节PRC2复合物的形成来拮抗STAT1启动子上H3K27me3的沉积，从而上调STAT1的表达。DDX18-STAT1轴增强了癌细胞的干细胞特性、PD-L1表达的上调、T淋巴细胞的聚集和过度激活，以及在高度成瘤性和免疫抑制性的胰腺TME。© 2023. 作者（或作者团队）在Springer Nature Limited独家许可下。

Pancreatic ductal adenocarcinoma (PDAC) resists to current treatments due to its inherent tumor heterogeneity, therapy-resistant cancer stem/initiating cells survival, and immune evasion in the immunosuppressive tumor microenvironment (TME). Here, the results show that clinical PDAC and adjacent tissues undergo distinct chromatin remodeling. Multiple omics analysis revealed DEAD-box RNA helicase 18 (DDX18), a carcinogenic gene with similar H3K4me3 profile, is up-regulated and correlates with poor survival in PDAC patients. We validated that DDX18 deposits on the STAT1 promoter region and counteracts H3K27me3 deposition on the STAT1 promoter sequence by modulating the formation of the PRC2 complex to up-regulate the expression of STAT1, which results in the up-regulation of PD-L1 expression, T lymphocyte accumulation and overactivation in the highly desmoplastic and immunosuppressive pancreatic TME. DDX18-STAT1 axis inhibition also affects stemness of cancer cells, epithelial-mesenchymal transition (EMT) and disrupts the immunosuppressive TME simultaneously, producing sustained remissions of aggressive PDAC by synergizing with anti-PD-L1 therapy. Combining DDX18 inhibition with anti-PD-L1 immunochemotherapy to treat PDAC patients will pave a new way for clinical treatment of patients with PDAC. This study found that clinical PDAC and adjacent pancreatic tissues undergo distinct chromatin remodeling featured by the upregulation of DEAD-box RNA helicase 18 (DDX18). We further validated that DDX18 deposits on the STAT1 promoter region and counteracts H3K27me3 deposition on the STAT1 promoter by modulating the formation of the PRC2 complex to up-regulate the expression of STAT1. DDX18-STAT1 axis enhances the stemness of cancer cells, the upregulation of PD-L1 expression, T lymphocyte accumulation and overactivation in the highly desmoplastic and immunosuppressive pancreatic TME.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.