TET3 is a common epigenetic immunomodulator of pathogenic macrophages.

Through a combination of single-cell/single-nucleus RNA-sequencing (sc/snRNA-seq) data analysis, immunohistochemistry, and primary macrophage studies, we have identified pathogenic macrophages characterized by TET3 overexpression (Toe-Macs) in three major human diseases associated with chronic inflammation: metabolic dysfunction-associated steatohepatitis (MASH), non-small cell lung cancer (NSCLC), and endometriosis. These macrophages are induced by common factors present in the disease microenvironment (DME). Crucially, the universal reliance on TET3 overexpression among these macrophages enables their selective elimination as a single population, irrespective of heterogeneity in other molecular markers. In mice, depleting these macrophages via myeloid-specific Tet3 knockout markedly mitigates disease progression and the therapeutic effects are recapitulated pharmacologically using a TET3-specific small molecule degrader. Through an unexpected mode of action, TET3 epigenetically regulates expression of multiple genes key to the generation and maintenance of an inflammatory/immunosuppressive DME. We propose that Toe-Macs are a unifying feature of pathogenic macrophages that could be therapeutically targeted to treat MASH, NSCLC, endometriosis, and potentially other chronic inflammatory diseases.