HBV-associated hepatocellular carcinomas inhibit antitumor CD8+ T cell via the long noncoding RNA HDAC2-AS2

Yanan Gao, Zhenxing Zhang, Xuetao Huang, Maojun You, Chengzhi Du, Nan Li, Yajing Hao, Kang Wang, Xiang Ding, Fuquan Yang, Shu-qun Cheng, Jianjun Luo (), Runsheng Chen () and Pengyuan Yang ()
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Yanan Gao: Chinese Academy of Sciences
Zhenxing Zhang: Chinese Academy of Sciences
Xuetao Huang: Chinese Academy of Sciences
Maojun You: Chinese Academy of Sciences
Chengzhi Du: Chinese Academy of Sciences
Nan Li: Naval Medical University
Yajing Hao: Chinese Academy of Sciences
Kang Wang: Naval Medical University
Xiang Ding: University of Chinese Academy of Sciences
Fuquan Yang: University of Chinese Academy of Sciences
Shu-qun Cheng: Naval Medical University
Jianjun Luo: Chinese Academy of Sciences
Runsheng Chen: Chinese Academy of Sciences
Pengyuan Yang: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Extracellular vesicles (EV) are critical mediators of intercellular communication within the tumor microenvironment, and cancer-cell-secreted EVs often facilitate cancer progression. Here we show that in HBV-associated HCC, tumor-cell-derived EVs contain a TGFβ-inducible long noncoding RNA, termed HDAC2-AS2. EVs enriched with HDAC2-AS2 facilitate cancer progression by suppressing cytotoxicity of intra-tumor CD8+ T cells. Mechanistically, in activated cytotoxic CD8+ T cells, translocation of the transcription factor cyclin-dependent kinase 9 (CDK9), to the cytoplasm is critical for functional integrity. HDAC2-AS2 targets and blocks cytosolic CDK9, and this results in exhaustion of PD-1+CD8+ T cells and suppression of IFN-γ+CD8+ T cell cytotoxicity. Notably, we demonstrate that low CDK9 and high HDAC2-AS2 expressions are associated with poor survival of HCC, which can be rescued by anti-PD-1 therapy. These findings emphasize the significance of tumor-derived EVs in suppressing antitumor CD8+ T cell immunity to promote tumorigenesis, and highlight extracellular HDAC2-AS2 as a promising biomarker and therapeutic target for HCC.

Date: 2025
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DOI: 10.1038/s41467-025-57367-8

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