Microplastic-Induced Macrophage Dysfunction Drives Lung Tumor Progression through Glutathione Imbalance

High Resolution Image Download MS PowerPoint Slide Microplastics (MPs) are emerging contaminants whose immunological consequences remain poorly defined. Here, we investigated MP-induced immune responses using bone marrow-derived macrophages and a lung tumor model to delineate how MPs modulate tumor immunity. MPs triggered TLR2- and TLR4-dependent signaling pathways in macrophages, which initiated AP-1 signaling and lysosomal destabilization, followed by mitochondrial depolarization and excessive reactive oxygen species production. Despite NRF2 pathway activation, GPX1 and GPX3 were selectively suppressed, revealing a paradoxical uncoupling of glutathione metabolism that precipitated macrophage ferroptosis. In vivo, orally ingested MPs accumulated across multiple organs. In the lungs of tumor-bearing mice, MP exposure led to a time-dependent remodeling of the immune microenvironment, characterized by marked infiltration of M1-like macrophages and functional impairment of lymphocytes at later stages, which was accompanied by increased tumor burden. These findings identify an immune–redox–ferroptosis axis driven by glutathione imbalance and suggest redox disruption as a mechanistic link between microplastic exposure and tumor progression.