浸润人类肿瘤的调节性T细胞（Treg）相比于外周血Treg细胞（PBTRs），呈现出更强的免疫抑制活性，因此阻碍了有效的抗肿瘤免疫反应的诱导。以往的转录组研究已经鉴定出一组在肿瘤浸润的Treg细胞（TITRs）中具有保守性的基因，但是TITRs的表观遗传学特征目前尚未完全解析。本研究采用ATAC-seq和 CUT&Tag检测技术，整合转录组文件，鉴定TITRs中的功能性调节元件。我们观察到TITRs和PBTRs之间染色质可及性和增强子谱系存在全局差异。我们鉴定了TITRs中两种类型的活性增强子形成。H3K4me1预设增强子在肿瘤微环境刺激下，即准备激活。我们发现AP-1家族基序在TITRs的增强子区域中富集。最后，我们验证了c-Jun结合在调控区域来调控TITRs的标志基因，并且AP-1在体外Treg细胞激活中是必要的。高c-Jun表达与人类HCC的不良生存率有关。总的来说，我们的结果为了解AP-1介导的TITRs激活机制提供了见解，可望用于开发针对肝癌治疗中的TITRs的新疗法。 © 2023作者，独家授权给 Springer Nature Switzerland AG。

Regulatory T (Treg) cells that infiltrate human tumors exhibit stronger immunosuppressive activity compared to peripheral blood Treg cells (PBTRs), thus hindering the induction of effective antitumor immunity. Previous transcriptome studies have identified a set of genes that are conserved in tumor-infiltrating Treg cells (TITRs). However, epigenetic profiles of TITRs have not yet been completely deciphered. Here, we employed ATAC-seq and CUT&Tag assays to integrate transcriptome profiles and identify functional regulatory elements in TITRs. We observed a global difference in chromatin accessibility and enhancer landscapes between TITRs and PBTRs. We identified two types of active enhancer formation in TITRs. The H3K4me1-predetermined enhancers are poised to be activated in response to tumor microenvironmental stimuli. We found that AP-1 family motifs are enriched at the enhancer regions of TITRs. Finally, we validated that c-Jun binds at regulatory regions to regulate signature genes of TITRs and AP-1 is required for Treg cells activation in vitro. High c-Jun expression is correlated with poor survival in human HCC. Overall, our results provide insights into the mechanism of AP-1-mediated activation of TITRs and can hopefully be used to develop new therapeutic strategies targeting TITRs in liver cancer treatment.© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.