Targeting PRMT3 Impairs Methylation and Oligomerization of HSP60 to Boost Anti-tumor Immunity by Activating cGAS/Sting Signaling

Authors

Yunxing Shi
Zongfeng Wu
Shaoru Liu
Dinglan Zuo
Yi Niu
Yuxiong Qiu
Liang Qiao
Wei He
Jiliang Qiu
Yunfei Yuan
Guocan Wang
Binkui Li

Publication Date

9-10-2024

Journal

Nature Communications

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.

Keywords

Animals, Protein-Arginine N-Methyltransferases, Membrane Proteins, Nucleotidyltransferases, Humans, Mice, Carcinoma, Hepatocellular, Signal Transduction, Liver Neoplasms, Chaperonin 60, Cell Line, Tumor, Methylation, Immune Checkpoint Inhibitors, CD8-Positive T-Lymphocytes, Mitochondria, Mice, Inbred C57BL, DNA, Mitochondrial, Interferon-gamma, Male

Comments

Associated Data

PMID: 39256398