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.