SENP3 inhibition suppresses hepatocellular carcinoma progression and improves the efficacy of anti-PD-1 immunotherapy

Peng Wang; Jiannan Qiu; Yuan Fang; Songmao Li; Kua Liu; Yin Cao; Guang Zhang; Zhongxia Wang; Xiaosong Gu; Junhua Wu; Chunping Jiang

doi:10.1038/s41418-024-01437-9

SENP3 inhibition suppresses hepatocellular carcinoma progression and improves the efficacy of anti-PD-1 immunotherapy

Cell Death Differ. 2025 Jan 4. doi: 10.1038/s41418-024-01437-9. Online ahead of print.

Authors

Peng Wang^#^{1

2

3}, Jiannan Qiu^#^{1

2}, Yuan Fang^#⁴, Songmao Li^#⁵, Kua Liu^{2

3}, Yin Cao¹, Guang Zhang¹, Zhongxia Wang¹, Xiaosong Gu^{1

2}, Junhua Wu^{2

3}, Chunping Jiang^{6

7

8}

Affiliations

¹ Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
² Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China.
³ State Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.
⁴ Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
⁵ Department of Immunology, Key Laboratory of Immune Microenvironment and Disease,, Nanjing Medical University, Nanjing, China.
⁶ Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. chunpingjiang@nju.edu.cn.
⁷ Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China. chunpingjiang@nju.edu.cn.
⁸ Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China. chunpingjiang@nju.edu.cn.

^# Contributed equally.

PMID: 39755756
DOI: 10.1038/s41418-024-01437-9

Abstract

The importance of SUMOylation in tumorigenesis has received increasing attention, and research on therapeutic agents targeting this pathway has progressed. However, the potential function of SUMOylation during hepatocellular carcinoma (HCC) progression and the underlying molecular mechanisms remain unclear. Here, we identified that SUMO-Specific Peptidase 3 (SENP3) was upregulated in HCC tissues and correlated with a poor prognosis. Multiple functional experiments demonstrated that SENP3 promotes the malignant phenotype of HCC cells. Mechanistically, SENP3 deSUMOylates RACK1 and subsequently increases its stability and interaction with PKCβII, thereby promoting eIF4E phosphorylation and translation of oncogenes, including Bcl2, Snail and Cyclin D1. Additionally, tumor-intrinsic SENP3 promotes the infiltration of tumor-associated macrophages (TAMs) while reducing cytotoxic T cells to facilitate immune evasion. Mechanistically, SENP3 promotes translation of CCL20 via the RACK1 /eIF4E axis. Liver-specific knockdown of SENP3 significantly inhibits liver tumorigenesis in a chemically induced HCC model. SENP3 inhibition enhances the therapeutic efficacy of PD-1 blockade in an HCC mouse model. Collectively, SENP3 plays cell-intrinsic and cell-extrinsic roles in HCC progression and immune evasion by modulating oncogene and cytokine translation. Targeting SENP3 is a novel therapeutic target for boosting HCC responsiveness to immunotherapy.