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

Yunxing Shi, Zongfeng Wu, Shaoru Liu, Dinglan Zuo, Yi Niu, Yuxiong Qiu, Liang Qiao, Wei He, Jiliang Qiu, Yunfei Yuan (), Guocan Wang () and Binkui Li ()
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Yunxing Shi: Sun Yat-Sen University Cancer Center
Zongfeng Wu: Sun Yat-Sen University Cancer Center
Shaoru Liu: Sun Yat-Sen University Cancer Center
Dinglan Zuo: Sun Yat-Sen University Cancer Center
Yi Niu: Sun Yat-Sen University Cancer Center
Yuxiong Qiu: Sun Yat-Sen University Cancer Center
Liang Qiao: Sun Yat-Sen University Cancer Center
Wei He: Sun Yat-Sen University Cancer Center
Jiliang Qiu: Sun Yat-Sen University Cancer Center
Yunfei Yuan: Sun Yat-Sen University Cancer Center
Guocan Wang: The University of Texas MD Anderson Cancer Center
Binkui Li: Sun Yat-Sen University Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52170-3

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