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Targeting PRMT3 impairs methylation and oligomerization of HSP60 to boost anti-tumor immunity by activating cGAS/STING signaling

Affiliations
  • 1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China.
  • 2Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China.
  • 3Department of Colorectal Surgery, Guangdong Institute of Gastroenterology, and Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 4State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China. yuanyf@mail.sysu.edu.cn.
  • 5Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China. yuanyf@mail.sysu.edu.cn.
  • 6Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. gwang6@mdanderson.org.
  • 7State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China. libk@sysucc.org.cn.
  • 8Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China. libk@sysucc.org.cn.

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September 10, 2024

Abstract

Immune checkpoint blockade (ICB) has emerged as a promising therapeutic option for hepatocellular carcinoma (HCC), but resistance to ICB occurs and patient responses vary. Here, we uncover protein arginine methyltransferase 3 (PRMT3) as a driver for immunotherapy resistance in HCC. We show that PRMT3 expression is induced by ICB-activated T cells via an interferon-gamma (IFNγ)-STAT1 signaling pathway, and higher PRMT3 expression levels correlate with reduced numbers of tumor-infiltrating CD8 T cells and poorer response to ICB. Genetic depletion or pharmacological inhibition of PRMT3 elicits an influx of T cells into tumors and reduces tumor size in HCC mouse models. Mechanistically, PRMT3 methylates HSP60 at R446 to induce HSP60 oligomerization and maintain mitochondrial homeostasis. Targeting PRMT3-dependent HSP60 methylation disrupts mitochondrial integrity and increases mitochondrial DNA (mtDNA) leakage, which results in cGAS/STING-mediated anti-tumor immunity. Lastly, blocking PRMT3 functions synergize with PD-1 blockade in HCC mouse models. Our study thus identifies PRMT3 as a potential biomarker and therapeutic target to overcome immunotherapy resistance in HCC.

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