Hypoxia-induced RCOR2 promotes macrophage M2 polarization and CD8 + T-cell exhaustion by enhancing LIF transcription in hepatocellular carcinoma

作者：Wenbo Jia, Jinyi Wang, Weiming Yang, Zhijie Ding, Litao Liang, Chao Xu, Yanzhi Feng, Qingpeng Lv, Zhu Deming, Wenhu Zhao, Xiangyu Ling, Yong Yan, Xiaoming Ai, Yongping Zhou, Lianbao Kong, Wenzhou Ding · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2025-012314 · 被引用次数：7 · 研究领域：Immune cells in cancer、Cancer, Hypoxia, and Metabolism、Hippo pathway signaling and YAP/TAZ

BACKGROUND: The hypoxic microenvironment plays a crucial role in regulating the progression of hepatocellular carcinoma (HCC) and facilitating immune evasion. It is essential to gain a more comprehensive understanding of the pathways through which hypoxia influences HCC progression and immune evasion. METHODS: We employed RNA sequencing, The Cancer Genome Atlas (TCGA) data analysis, clinical data analysis of HCC, and tissue microarray immunohistochemical analysis to identify key genes associated with hypoxia regulation and immune evasion. We investigated the biological functions of REST corepressor 2 (RCOR2) in tumor progression and immune evasion through mass cytometry, multiplex immunofluorescence, an orthotopic liver transplantation tumor model, in vitro co-culture systems, flow cytometry, and immunohistochemical analysis. Additionally, we used molecular techniques such as RNA sequencing, chromatin immunoprecipitation sequencing, and mass spectrometry to gain deeper insights into the potential molecular mechanisms underlying RCOR2. RESULTS: T cells. Mechanistically, the hypoxic microenvironment increases the expression of RCOR2 through hypoxia-inducible factor 1-alpha. Concurrently, this microenvironment inhibits the ubiquitin-mediated degradation of RCOR2 by promoting its sumoylation, which facilitates its translocation to the nucleus. The sumoylation of RCOR2 further enhances the transcriptional activity of leukemia inhibitory factor (LIF). LIF, derived from HCC, contrib...