Epigenetic regulation of gene expression in cancer cells has been extensively studied in recent decades, resulting in the FDA approval of multiple epigenetic agents for treating different cancer types. Recent studies have revealed novel roles of epigenetic dysregulation in altering the phenotypes of immune cells and tumor-associated stromal cells, including fibroblasts and endothelial cells. As a result, epigenetic dysregulation of these cells reshapes the tumor microenvironment (TME), changing it from an antitumor environment to an immunosuppressive environment. Here, we review recent studies demonstrating how specific epigenetic mechanisms drive aspects of stromal and immune cell differentiation with implications for the development of solid tumor therapeutics, focusing on the pancreatic ductal adenocarcinoma (PDA) TME as a representative of solid tumors. Due to their unique ability to reprogram the TME into a more immunopermissive environment, epigenetic agents have great potential for sensitizing cancer immunotherapy to augment the antitumor response, as an immunopermissive TME is a prerequisite for the success of cancer immunotherapy but is often not developed with solid tumors. The idea of combining epigenetic agents with cancer immunotherapy has been tested both in preclinical settings and in multiple clinical trials. In this review, we highlight the basic biological mechanisms underlying the synergy between epigenetic therapy and immunotherapy and discuss current efforts to translate this knowledge into clinical benefits for patients.

近几十年来，癌细胞基因表达的表观遗传调控得到了广泛的研究，导致 FDA 批准了多种表观遗传药物用于治疗不同的癌症类型。最近的研究揭示了表观遗传失调在改变免疫细胞和肿瘤相关基质细胞（包括成纤维细胞和内皮细胞）表型方面的新作用。结果，这些细胞的表观遗传失调重塑了肿瘤微环境（TME），将其从抗肿瘤环境转变为免疫抑制环境。在这里，我们回顾了最近的研究，这些研究表明特定的表观遗传机制如何驱动基质和免疫细胞分化，并对实体瘤治疗的发展产生影响，重点关注作为实体瘤代表的胰腺导管腺癌（PDA）TME。由于其将 TME 重新编程到更免疫允许的环境的独特能力，表观遗传剂在使癌症免疫治疗敏感以增强抗肿瘤反应方面具有巨大的潜力，因为免疫允许的 TME 是癌症免疫治疗成功的先决条件，但通常不是用固体药物来开发的。肿瘤。将表观遗传学药物与癌症免疫疗法相结合的想法已经在临床前环境和多项临床试验中得到了检验。在这篇综述中，我们强调了表观遗传疗法和免疫疗法之间协同作用的基本生物学机制，并讨论了当前将这些知识转化为患者临床益处的努力。