Ambient PM2.5 exposure is associated with clear cell renal cell carcinoma aggressiveness and promotes tumor progression through ROS-mediated AKT/HIF-2α signaling.

Abstract

Ambient fine particulate matter (PM2.5) is an established environmental health hazard, but its role in clear cell renal cell carcinoma (ccRCC) progression remains incompletely understood. This study integrated epidemiological analysis, mechanistic experiments, transcriptomic profiling, and clinical tissue validation to investigate the association between ambient PM2.5 exposure and ccRCC aggressiveness. Among 1410 patients with pathologically confirmed ccRCC, long-term residential PM2.5 exposure during the 36 months before diagnosis was estimated using geocoded addresses and the Tracking Air Pollution in China dataset. Each 10 μg/m3 increase in PM2.5 exposure was independently associated with advanced AJCC stage (adjusted OR, 1.42; 95% CI, 1.15-1.74) and higher WHO/ISUP grade (adjusted OR, 1.36; 95% CI, 1.12-1.65). Locally collected winter ambient PM2.5 exhibited irregular morphology, heterogeneous aggregation, and complex chemical composition. In vitro and in vivo, PM2.5 enhanced ccRCC cell proliferation, clonogenic growth, migration, invasion, epithelial-mesenchymal transition-like remodeling, and tumor growth. Mechanistically, PM2.5 increased intracellular and mitochondrial ROS, activated PI3K/AKT signaling, enhanced HIF-2α protein stability and nuclear accumulation, and increased HIF-related transcriptional output. Complementary antioxidant, pharmacological, genetic, and rescue experiments supported a functional contribution of the ROS/AKT/HIF-2α axis to PM2.5-associated malignant phenotypes. Transcriptomic profiling identified ROS-responsive genes enriched in oxidative stress, PI3K/AKT signaling, hypoxia response, extracellular matrix organization, and EMT-related pathways. PM2.5 also activated NF-κB-related inflammatory signaling, suggesting an additional ROS-responsive inflammatory response. Clinical ccRCC tissues from patients with higher PM2.5 exposure showed increased HIF-2α and Ki-67 expression together with EMT-related protein alterations. Collectively, these findings indicate that long-term ambient PM2.5 exposure is associated with more aggressive ccRCC and support a model in which oxidative stress contributes, at least in part, to tumor progression through AKT/HIF-2α signaling.