Dysregulation of SUSD2-CLDN18.2-mediated cell adhesion contributes to lung adenocarcinoma progression associated with chronic low-dose nanoplastics exposure

Emerging evidence suggests that inhaled microplastics (MPs) and nanoplastics (NPs), which can accumulate in the lungs, may exacerbate pulmonary diseases. Due to their small size, high surface reactivity, and ability to penetrate deep into respiratory tissues, NPs are particularly prone to inducing adverse biological effects that may be closely linked to lung cancer. However, the role of long-term NP accumulation in lung cancer progression and the underlying mechanisms remain poorly understood. Notably, most existing studies rely on high-dose, short-term exposure models that do not accurately reflect real-world, low-level, chronic human exposure. To address this gap, we established a chronic exposure model using A549 lung adenocarcinoma (LUAD) cells continuously exposed to 2.5 μg/mL polystyrene (PS)-NPs over six months. Chronic PS-NP exposure significantly enhanced malignant phenotypes, including increased proliferation, migration, and invasion, and downregulated SUSD2, a gene linked to LUAD progression. Importantly, SUSD2 overexpression effectively reversed these tumor-promoting effects induced by PS-NPs exposure. Multi-omics analyses suggest that SUSD2 role is closely associated with the regulation of cell adhesion molecule (CAM). Further mechanistic investigation reveals that SUSD2 exerts its tumor-suppressive effects via modulating the CAMs pathway through regulation of CLDN18.2, thereby influencing cell adhesion dynamics and contributing to PS-NP-associated LUAD progression. Consistent with these findings, analysis of clinical data from LUAD patients demonstrate both SUSD2 and CLDN18.2 expression are significantly correlated with tumor progression and clinical outcomes, highlighting their potential as biomarkers and therapeutic targets. Our findings demonstrate the oncogenic potential of chronic PS-NPs exposure and provide novel mechanistic insights into the role of the SUSD2-CLDN18.2 signaling axis in mediating this effect. These results further support the evidence linking environmental NPs with tumor progression and provide a basis for assessing their long-term health impacts.