Targeting PRMT3 impairs methylation and oligomerization of HSP60 to boost anti-tumor immunity by activating...

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Immune checkpoint blockade (ICB) shows promise for hepatocellular carcinoma (HCC) treatment.
• However, variable patient responses and resistance limit ICB efficacy.
• Identifying mechanisms of resistance is crucial for improving HCC immunotherapy.

Purpose of the Study:

• To investigate the role of protein arginine methyltransferase 3 (PRMT3) in HCC immunotherapy resistance.
• To elucidate the molecular mechanisms by which PRMT3 affects anti-tumor immunity.
• To evaluate PRMT3 as a potential therapeutic target for overcoming ICB resistance in HCC.

Main Methods:

• Analysis of PRMT3 expression in HCC patient samples and correlation with ICB response.
• Investigating PRMT3 induction by interferon-gamma (IFNγ) and STAT1 signaling.
• Utilizing genetic depletion and pharmacological inhibition of PRMT3 in HCC mouse models.
• Exploring PRMT3's mechanism involving HSP60 methylation, mitochondrial homeostasis, and cGAS/STING pathway activation.

Main Results:

• PRMT3 expression is upregulated by ICB-activated T cells via IFNγ-STAT1 signaling.
• Higher PRMT3 levels correlate with reduced CD8+ T cell infiltration and poorer ICB response.
• PRMT3 inhibition increases T cell influx, reduces tumor size, and enhances anti-tumor immunity.
• PRMT3 methylates HSP60, maintaining mitochondrial integrity; its inhibition leads to mtDNA leakage and cGAS/STING activation.
• Blocking PRMT3 synergizes with PD-1 blockade in HCC models.

Conclusions:

• PRMT3 acts as a key driver of immunotherapy resistance in HCC.
• Targeting PRMT3 can restore T cell-mediated anti-tumor immunity.
• PRMT3 is a potential biomarker and therapeutic target to improve ICB efficacy in HCC.