Molecular epidemiology targeting the impact of particulate matter ≤ 2.5 μm in aerodynamic diameter (PM2.5) on pro-oncogenic signaling has been sparsely reported from the Indian industrial belt. This study investigated the effect of seasonal variation in PM2.5 on pro-oncogenic drivers in the pulmonary and systemic cellular environments of a thermal power plant participants in West Bengal, India during 2021–2022. PM2.5 levels were significantly higher during spring than monsoon, coinciding with reduced hemoglobin and lung function indices. Linear Mixed-Effects Regression (LMER) confirmed that elevated PM2.5 exposure was significantly associated with increased inflammatory response, enhanced matrix metalloproteinase-9 (MMP-9) activity, and upregulation of the epidermal growth factor receptor (EGFR)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) cascade, along with downregulation of …