Lung cancer in never-smokers (LCINS) is the eighth most common cause of cancer death in the UK. Such patients bear distinct clinical and molecular characteristics compared to lung cancer in smokers which include EGFR mutations. The current study explores the relationship between air pollutants and EGFR-driven mutations in the context of lung adenocarcinoma (LUAD). Particulate matter (PM) of size  2.5 m (PM2.5) can travel deep into the lungs. The current study proposes that the air pollutants may promote inflammatory changes in the lung tissue microenvironment that permit pre-existing mutated clones to expand, consistent with the two-stage carcinogenesis model of initiation and promotion. Methodology: Researchers used data from three countries to explore different ranges of PM2.5 air pollution and ethnicities. They analyzed 3 years and 20 years of PM2.5 cumulative exposure. They used data from PEACE, TRACERx, UK Biobank and NDRS datasets for the England population. They also used South Korea dataset and Chang Gung Research Database of Taiwan. They performed mutational profiles by ddPCR, MiSeq, Duplex-Seq, whole genome sequencing, RNA sequencing. They also used mice models. Results: Researchers found that the frequency of EGFR-driven lung cancer cases was significantly higher after 3 years of high air pollutant exposure compared with low exposure. However, this association was not so strong for 20 years of exposure. It means 3 years of high PM2.5 exposure is enough for EGFR-driven lung cancer to arise. An analysis including all participants, irrespective of EGFR status, showed that PM2.5 levels were associated with lung cancer incidence. Smoking and high PM2.5 status may have a combined effect on lung cancer. Researchers used genetically engineered mouse models of LUAD and induced expression of oncogenic human EGFR (L858R) in mouse lungs. Mice were exposed to PM or PBS (control) for 3 weeks and tumor burden was assessed after 10 weeks. An increase in the number of pre-invasive neoplasias was observed in PM-exposed mice. Exposure to PM before induction of EGFR (L858R) also increased the number of pre-invasive neoplasias. The spatial analysis of clonal dynamics showed that the fraction of EGFR (L858R) cells grew into clusters and their numbers increased within clusters after the PM-exposed period. PM increases number of EGFR mutant cells and also the proliferation rate of mutant cells within early lesions. Whole genome sequencing revealed no enhancement of mutagenesis on exposure to PM. After exposure to PM, the proportion of interstitial macrophages and PD-L1 expression increased, irrespective of EGFR status. It leads to the hypothesis that transient PM exposure is associated with enhanced and sustained lung macrophage infiltration beyond the period of PM exposure. RNA-seq data analysis showed that EGFR mutation is responsible for 38% variance of gene expression difference between control and mutated mice exposed to PM. In mutated mice, PM exposure led to an upregulation of genes known to regulate macrophage recruitment, including those that encode interleukin-1β (IL-1β). AT2 cells are known as the probable cell of origin of lung adenocarcinoma. EGFR (L858R) mutated AT2 cells are transcriptionally reprogrammed to this progenitor cell state following PM exposure. Researchers isolated AT2 cells from mice, induced EGFR (L858R) expression, and exposed them in vivo to either PM or PBS. They observed PM exposed macrophages enhanced organoid formation efficiency. It indicates that PM-induced inflammation arises from macrophages. On the other hand, treatment of EGFR mutant AT2 cells in IL-1 resulted with larger organoids. Also, treatment of PM exposed mutated mice with anti-IL-1 antibody attenuated EGFR driven LUAD formation. It establishes PM exposed macrophages can induce a progenitor-like state in EGFR mutant AT2 cells. However, it is also observed that EGFR mutations can also be present in normal lung tissue of patients. Also, 16% (3 out of 19) of healthy people bear EGFR mutations in their lung tissues. Anthracosis is known to act as a surrogate marker of exposure to air pollution. An association between anthracosis and increased variant allele frequencies of EGFR mutations was also observed. Apart from EGFR mutation status, the current study also explored KRAS mutation status. It reported that KRAS mutant clones may be more highly selected than EGFR mutant clones in healthy lungs of ever-smokers. Also, there was a significant correlation between age and mutation count. Discussion: It provides a balanced study of cohorts considering sex, geographically and ethnically distinct populations. It reveals PM exposure contributes to the geographical disparities of EGFR driven lung cancer. Conclusion: Researchers have performed a comprehensive analysis and proposed that PM can trigger the expansion of preexisting mutant lung cells through an inflammatory axis which can be treated. The temporal analysis shows that three years of PM2.5 exposure is sufficient to develop EGFR driven LUAD. Impact of the research: It reveals PM2.5 induces an altered progenitor state in EGFR mutant cells through the macrophage release of IL-1β, which promotes lung cancer. It provides a public health mandate to control air pollution specifically to the urban area.