TET3 is a common epigenetic immunomodulator of pathogenic macrophages

Area of Science:

• Immunology
• Molecular Biology
• Epigenetics

Background:

• Chronic inflammation underlies major diseases like MASH, NSCLC, and endometriosis.
• Pathogenic macrophages contribute to disease progression and the inflammatory microenvironment.
• Identifying common molecular drivers across distinct inflammatory diseases is crucial for therapeutic development.

Purpose of the Study:

• To identify a common pathogenic macrophage population across metabolic dysfunction-associated steatohepatitis (MASH), non-small cell lung cancer (NSCLC), and endometriosis.
• To investigate the role of TET3 in the development and function of these pathogenic macrophages.
• To explore the therapeutic potential of targeting TET3-overexpressing macrophages.

Main Methods:

• Single-cell/single-nucleus RNA-sequencing (sc/snRNA-seq) analysis.
• Immunohistochemistry.
• Primary macrophage studies in vitro and in vivo.
• Myeloid-specific Tet3 knockout mouse models.
• Pharmacological inhibition using a TET3-specific small molecule degrader.

Main Results:

• Identified TET3-overexpressing macrophages (Toe-Macs) as a shared pathogenic cell type in MASH, NSCLC, and endometriosis.
• Demonstrated that Toe-Macs are induced by common factors within the disease microenvironment (DME).
• Showed that depleting Toe-Macs in mice ameliorates disease progression, with similar effects observed using a TET3 degrader.
• Revealed that TET3 epigenetically regulates genes critical for an inflammatory/immunosuppressive DME.

Conclusions:

• Toe-Macs represent a unifying pathogenic macrophage population across diverse chronic inflammatory diseases.
• Targeting TET3 overexpression offers a potential therapeutic strategy for MASH, NSCLC, endometriosis, and other inflammatory conditions.
• TET3 plays a key epigenetic role in shaping the disease microenvironment through macrophage regulation.