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journal article·2025-02Open access

Targeting Deltex E3 Ubiquitin Ligase 2 Inhibits Tumor‐associated Neutrophils and Sensitizes Hepatocellular Carcinoma Cells to Immunotherapy

Xiaoling Wu, Jiafeng Chen, Yiran Chen, Shushu Song, Yuan Fang, Shengwei Mao, Jun Gao, Guiqi Zhu, Weifeng Qu, Qianfu Zhao, Rui Yang, Zhiqi Guan, Tianhao Chu, Yichao Bu, Yi Wang, Fangyu Chen, Jian Zhou, Jia Fan, Zheng Tang, Weiren Liu, Yuanyuan Ruan, Yinghong Shi

Advanced Science· Volume 12· Issue 7
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Source abstract

Abstract

Abstract Several E3 ligases have been found to affect the immune microenvironment of hepatocellular carcinoma (HCC) and lead to the resistance of immunotherapy. In this study, genes of E3 ligases are screened based on The Cancer Genome Atlas (TCGA) dataset. Through cytometry by time of flight (CyTOF), flow cytometry, and further experiments, Deltex E3 ubiquitin ligase 2 (DTX2) in HCC cells is identified to promote the infiltration and polarization of tumor‐associated neutrophils (TANs) with a protumor phenotype, thus attenuating the infiltration and cytotoxicity of CD8+ T cells partially through C‐X‐C motif chemokine 2 (CXCL2) and C‐X‐C motif chemokine 6 (CXCL6). Mechanistically, DTX2 can interact with histone H2B and promote its monoubiquitination at lysine120 (H2BK120ub1), thereby increasing CXCL2 and CXCL6 transcription through histone epigenetic regulation. Different tumor models in vivo demonstrated that DTX2 inhibitor treatment inhibited tumor growth and sensitized HCC cells to the therapeutic effects of programmed cell death protein 1 (PD‐1) antibody. In summary, this study identifies DTX2 as a potential target for HCC immunotherapy.
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Research context

OpenAlex topics: Immune cells in cancer · Ubiquitin and proteasome pathways · Acute Myeloid Leukemia Research

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Liver Surgery and Transplantation Zhongshan Hospital Fudan University Shanghai 200032 China

Research Unit of Liver Cancer Recurrence and Metastasis Chinese Academy of Medical Sciences Beijing 100010 China

Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Shanghai 200032 China

Liver Cancer Institute Zhongshan Hospital Fudan University Shanghai 200032 China

Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Fudan University Shanghai 200032 China

Department of Radiation Oncology Zhongshan Hospital Affiliated to Fudan University Shanghai 200032 China

Institutes of Biomedical Sciences Fudan University Shanghai 200032 China

Shanghai Key Laboratory of Organ Transplantation Shanghai 200032 China

Funding

National Natural Science Foundation of China · National Key Research and Development Program of China · Shanghai Municipal Health Commission

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