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.

胰腺导管腺癌 (PDAC) 由于其固有的肿瘤异质性、治疗耐药的癌症干细胞/起始细胞存活以及免疫抑制肿瘤微环境 (TME) 中的免疫逃避，对当前的治疗产生抵抗。在这里，结果表明临床 PDAC 和邻近组织经历了明显的染色质重塑。多重组学分析显示，DEAD-box RNA 解旋酶 18 ( DDX18 ) 是一种与 H3K4me3 谱相似的致癌基因，该基因上调并与 PDAC 患者的生存率较差相关。我们验证了 DDX18 沉积在STAT1启动子区域上，并通过调节PRC2复合物的形成来上调 STAT1 的表达，从而抵消 H3K27me3 在 STAT1 启动子序列上的沉积，从而导致 PD-L1 表达上调，T高度促纤维增生和免疫抑制的胰腺 TME 中淋巴细胞积聚和过度激活。DDX18-STAT1 轴抑制还影响癌细胞的干性、上皮间质转化 (EMT)，并同时破坏免疫抑制性 TME，通过与抗 PD-L1 疗法协同作用，使侵袭性 PDAC 持续缓解。将DDX18抑制与抗PD-L1免疫化疗联合治疗PDAC患者将为PDAC患者的临床治疗开辟新的途径。