TET3-overexpressing macrophages are a unifying pathogenic feature with therapeutic potential in chronic inflammatory diseases

Increased activation of the NLRP3 inflammasome in immune cells, including macrophages, has been implicated in the pathogenesis of multiple chronic inflammatory diseases. Targeted depletion of macrophages has been explored as a cross-disease therapeutic strategy, but without subtype-specific markers, this strategy risks elimination of macrophages with homeostatic functions. In this study, Liu et al. identified a subpopulation of pathogenic macrophages, referred to as Toe-Macs, which are characterized by overexpression of the DNA demethylase TET3 in metabolic dysfunction-associated steatohepatitis (MASH), non-small cell lung cancer (NSCLC), and endometriosis. When induced into the disease microenvironment, Toe-Macs produced proinflammatory cytokines and chemokines. Selective elimination of Toe-Macs attenuated disease progression without any discernible side effects in mouse models of MASH and NSCLC. These findings highlight the role of Toe-Macs in the pathogenesis of chronic inflammatory diseases and provide a rationale for exploring TET3 as a therapeutic target.