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

Abstract

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.