IL23A acts as a pivotal mediator of PM2.5-induced lung tumorigenesis through the NF-κB pathway activation.

Many epidemiological studies have shown that long-term fine particulate matter (PM2.5) exposure significantly increases lung cancer incidence, but direct experimental evidence linking PM2.5 and lung carcinogenesis remains limited. Chronic inflammation has long been associated with increased cancer occurrence. However, studies on the inflammatory effects of PM2.5 in lung tumorigenesis and the underlying mechanisms remain incompletely understood. Our present work revealed that PM2.5 increased the levels of various proinflammatory cytokines, including interleukin-23 subunit alpha (IL23A), which potentiated the malignant behavior of lung epithelial cells. IL23A was significantly overexpressed in lung adenocarcinoma (LUAD) tissues, and its expression was negatively correlated with prognosis in non-smokers. Importantly, PM2.5 increased IL23A expression by activating the canonical NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) pathway in non-small cell lung cancer (NSCLC) cells, which was prevented by siRNA-mediated p65 knockdown or chemical inhibitor treatment. Moreover, neutralizing antibodies against IL23A dramatically suppressed the tumor formation and growth in orthotopic lung tumor mice treated with PM2.5, accompanied with a reduction in IL23A. Interestingly, an atypical secreted form of IL23A independent of the IL12B subunit in lung epithelial cells was identified. Collectively, our findings establish IL23A as both a functional mediator and a clinically valuable prognostic biomarker for PM2.5‑induced lung carcinogenesis, and highlight the NF-κB/IL23A axis as a promising therapeutic target for inflammation‑driven lung cancer.