USP22-mediated phagocytic evasion promotes immune escape in TP53-inactivated hepatocellular carcinoma.

Authors

Qifan Zhan, Qiaonan Shan, Jianan Xiang, Shengju Xu, Jiapei Wang, Jiongjie Yu, Guangjiang Jiang, Mingwei Gao, Shuqi Cai, Qianwei Ye, Chenyang Zhou, Nasha Qiu, Lu Yin, Mingcheng Wan, Tingting Feng, Haiyang Xie, Zi Yin, Rui Shao, Yishan Chen, Leiming Chen, Nan Wang, Jimin Liu, Wei Zhang, Yiren Hu, Zhe Tang, Shusen Zheng, Lixing Zhan, Xiao Xu, Sunbin Ling

Published in

Clinical and molecular hepatology. Oct 27, 2026. Epub Oct 27, 2026.

Abstract

Hepatocellular carcinoma (HCC) is characterized by an immunosuppressive tumor microenvironment. Here, we aimed to elucidate the tumor cell-intrinsic functions of ubiquitin-specific protease 22 (USP22) in the immune escape of HCC cells.
Autochthonous mouse models of HCC with either genetic Usp22 loss or Trp53 knockdown were used. In vitro and in vivo phagocytosis assays were performed to evaluate the interactions between HCC cells and macrophages. Multicolor fluorescence, spatial transcriptomics, immunoprecipitation and ubiquitination assays were used to explore the potential underlying mechanisms.
We observed that tumor cell-intrinsic USP22 inhibits the infiltration and anticancer function of tumoricidal macrophages in HCC. USP22 expression in HCC cells blocks their direct phagocytosis by tumoricidal macrophages. Mechanistically, CD24 (a known phagocytosis checkpoint) mediates USP22-induced suppression of phagocytosis. USP22 promotes the transcriptional expression of CD24 by deubiquitinating and stabilizing the transcription factor E2F7. Furthermore, wild-type p53 downregulates USP22 protein expression, whereas TP53 inactivation markedly upregulates USP22 protein expression. The USP22-E2F7-CD24 axis is responsible for mediating TP53-inactivation-induced phagocytic evasion and hepatocarcinogenesis. Mechanistically, USP22 proteins bind to one another and suppress ubiquitination at the K442 residue. The wild-type p53 protein disrupts this mutual deubiquitination, thereby facilitating USP22 degradation. Moreover, TNF secreted by tumoricidal macrophages promotes USP22 degradation by disrupting its self-stabilizing mechanism in a wild-type p53-dependent manner. Our findings indicate that USP22-E2F7-CD24 axis-mediated phagocytic evasion promotes immune escape in TP53-inactivated HCC.

PMID:
42935236
Bibliographic data and abstract were imported from PubMed on 27 Oct 2026.

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