IFNγ信号主要通过激活规范的JAK-STAT信号通路、转录因子和表观遗传修饰来介导，IFNγ信号通路的激活可提供一种新的肿瘤免疫治疗选择，但其结果仍存在争议。实际上，最近的研究表明，IFNγ相关免疫疗法的耐药性通常源于肿瘤细胞内在的异质性，其分子机制尚不清楚。因此，阐明肿瘤细胞内在异质性对IFNγ的响应将有助于改善免疫疗法的疗效。在这里，我们首先描述了在IFNγ刺激下的表观遗传重分布和转录组改变，并证明启动子区域中H3K4me3和H3K27Ac的外源增益主要促进了IFNγ介导的干扰素刺激基因的转录活性。此外，我们发现，PD-L1表达的细胞异质性在响应IFNγ时主要归因于细胞内在的H3K27me3水平。GSK-J4增强H3K27me3通过挽救CD8+ T细胞的肿瘤内细胞毒性，限制PD-L1hi肿瘤生长，这可能提供了克服胰腺癌对IFNγ基础免疫疗法免疫逃逸和耐药的治疗策略。版权所有©2023 Elsevier B.V.出版。

IFNγ signaling is mainly mediated through the activation of the canonical JAK-STAT signaling pathway, transcription factors, and epigenetic modifications. The activation of IFNγ signaling pathway may provide a novel option for tumor immunotherapy, but the outcomes remain controversial. In fact, recent studies suggest that the resistance to IFNγ-dependent immunotherapies is commonly derived from the tumor cell-intrinsic heterogeneity, the molecular mechanism of which remains elusive. Therefore, elucidating the tumor cell-intrinsic heterogeneity in response to IFNγ would be beneficial to improve the efficacy of immunotherapy. Here, we first delineated the epigenetic redistribution and transcriptome alteration in response to IFNγ stimulation, and demonstrated that ectopic gain of H3K4me3 and H3K27Ac at the promoter region mainly contributed to the enhancement of IFNγ-mediated transcriptional activity of interferon-stimulated genes (ISGs). Furthermore, we found that the cellular heterogeneity of PD-L1 expression in response to IFNγ was mainly attributed to cell-intrinsic H3K27me3 levels. Enhancement of H3K27me3 by GSK-J4 limited PD-L1hi tumor growth by salvaging the intratumoral cytotoxicity of CD8+ T cells, which may provide therapeutic strategies to overcome immune escape and resistance to IFNγ-based immunotherapies in pancreatic cancer.Copyright © 2023. Published by Elsevier B.V.