Targeting TFAM downregulation mediated mtDNA-NLRP3 pathway suppresses TAM infiltration and HCC progression

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Tumor-associated macrophages (TAMs) drive an immunosuppressive tumor microenvironment crucial for hepatocellular carcinoma (HCC) progression.
• TFAM, regulating mitochondrial DNA (mtDNA) replication, is often downregulated in HCC, but its role in TAM infiltration remains unclear.

Purpose of the Study:

• To investigate the role of TFAM downregulation and subsequent cytosolic mtDNA stress in regulating TAM infiltration within the HCC microenvironment.

Main Methods:

• Correlative analysis of TFAM and CD163 expression in HCC tissues.
• In vitro studies involving TFAM-downregulated HCC cells to assess mtDNA stress, NLRP3 inflammasome activation, cytokine production, and macrophage recruitment.
• In vivo experiments using DNase I, NLRP3 antagonists, and orthotopic mouse models of HCC.

Main Results:

• TFAM expression was decreased in HCC and correlated with CD163, a TAM marker.
• TFAM downregulation induced cytosolic mtDNA stress, activating the NLRP3 inflammasome and increasing IL-18 and IL-1β, which promoted M2-TAM recruitment and polarization.
• Inhibition of cytosolic mtDNA or NLRP3 activation suppressed M2-TAM infiltration in vitro and in vivo.
• Blocking the mtDNA-NLRP3 pathway reduced TAM infiltration and HCC progression in an orthotopic mouse model.

Conclusions:

• TFAM downregulation in HCC induces cytosolic mtDNA stress, activating the NLRP3 inflammasome.
• This pathway promotes M2-TAM infiltration, contributing to HCC progression.
• Targeting the cytosolic mtDNA-NLRP3 pathway presents a potential therapeutic strategy for HCC.