Chronic nanoplastics exposure drives lung cancer progression through ATF3/PCK2 axis-mediated rewiring of truncated gluconeogenesis.

Environmental factors are critical for lung cancer progression, and nanoplastics (NPs) pose evolving health risks. Due to small size, NPs are readily inhaled and accumulate in lung tissues, but their long-term impact on lung cancer remains unclear. This study used long-term cell culture and orthotopic lung cancer models exposed to environmentally relevant NPs doses to investigate oncogenic potentials. Our results show that prolonged NPs exposure enhances lung adenocarcinoma A549 cell proliferation, migration, and invasion in vitro and accelerates lung tumor progression in vivo. Transcriptomic analysis identified activating transcription factor-3 (ATF3), induced by the protein kinase RNA-like ER kinase (PERK) branch of the unfolded protein response (UPR) and endoplasmic reticulum stress (ERs), as a key driver. Mechanistically, ATF3 activation upon NPs exposure promotes cancer progression by upregulating mitochondrial phosphoenolpyruvate carboxykinase (PCK2), a rate-limiting enzyme in truncated gluconeogenesis and serine/glycine biosynthesis. The ATF3-PCK2 axis facilitates metabolic reprogramming through enhanced anabolic gluconeogenesis, promoting lung cancer malignant progression under NPs exposure. These findings establish NPs as environmental tumor promoters in lung cancer and elucidate a novel metabolic activation pathway underlying their oncogenic effects, providing mechanistic insights with implications for risk assessment, prevention, and therapeutic intervention.