Aged ZnO Nanoparticles Promote Breast Cancer Lung Metastasis by Remodeling the Pulmonary Microenvironment Through the CXCL10/Wnt/β‐Catenin Axis

Abstract

ABSTRACT Our previous work demonstrated that zinc oxide nanoparticles (ZnO NPs) undergo physicochemical transformations during environmental aging, forming a composite mixture of zinc hydroxide carbonate, nanosized ZnO, and Zn 2+ (termed aged ZnO NPs). Compared to their pristine counterparts, aged ZnO NPs exhibit significantly enhanced mutagenicity and malignant transformation capacity in mouse embryonic fibroblasts. However, their potential role in cancer initiation and progression in vivo remains unresolved. Here, we provide the first evidence that subchronic pulmonary exposure to aged ZnO NPs markedly accelerates lung metastasis and colony formation in a mouse model of breast cancer. Single‐cell transcriptomic profiling (scRNA‐seq) revealed that aged NPs remodel the metastatic microenvironment by recruiting M2 macrophages and myeloid‐derived suppressor cells, and by activating cancer‐associated fibroblasts. These findings were corroborated by analysis of public scRNA‐seq datasets. Mechanistically, CXCL10 derived from macrophages and fibroblasts was identified as a key mediator of metastasis via activation of the Wnt/β‐catenin pathway. Notably, pharmacological inhibition of the CXCL10/CXCR3 axis effectively attenuated NP‐induced metastasis. Collectively, this study uncovers the cellular and molecular mechanisms by which aged ZnO NPs potentiate breast cancer metastasis, highlighting the need to incorporate environmental aging processes into the risk assessment of nanomaterials.