Parkin modulates the hepatocellular carcinoma microenvironment by regulating PD-1/PD-L1 signalling

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Parkin-mediated mitophagy is crucial for clearing damaged mitochondria and inhibiting tumor development.
• The role of mitophagy in tumor immunity is increasingly recognized, but mechanisms remain unclear.

Purpose of the Study:

• To investigate Parkin's role in the immune microenvironment of carbon tetrachloride-induced liver tumors.
• To elucidate the mechanism by which Parkin influences tumor immunity via PD-1 expression.

Main Methods:

• Single-cell RNA sequencing of T lymphocytes and myeloid-derived cells.
• Western blot, immunofluorescence, and co-immunoprecipitation.
• Quantitative proteomic analysis.

Main Results:

• Parkin deficiency (Park2-/-) in mice led to severe liver damage, increased malignancy, and an immunosuppressive tumor microenvironment.
• Reduced cytotoxic CD8+ T cells and increased exhausted CD8+ T cells (PD-1+, Lag3+, Tigit+) were observed in Park2-/- mice.
• Increased M2-like macrophages and differential protein expression related to PD-1 and antigen presentation pathways were found in Parkin-deficient livers.
• Parkin deficiency decreased hepatic mitophagy, promoting liver cancer by creating an immunosuppressive microenvironment.

Conclusions:

• Parkin, an E3 ubiquitin ligase, degrades PD-1 in liver cancer, influencing anti-tumor immunity via the PD-1/PD-L1 pathway.
• Reintroducing Parkin or enhancing mitophagy can remodel the tumor microenvironment, activating anti-tumor immunity.
• Targeting Parkin or mitophagy presents a promising strategy to improve immunotherapy efficacy in hepatocellular carcinoma (HCC).