Looking through the particles: a narrative review of air pollution and lung cancer.

Introduction
Air pollution is a byproduct of industrialization, and as urban development increases in all countries, so too does the global burden of air pollution. Air pollution’s pathogenicity depends on its size and composition and can be broadly categorized into gaseous products or particulate matter (PM).
While various air pollutants, including volatile organic compounds and nitrogen oxides, have been associated with lung cancer risk, PM, specifically of size ≤2.5 µm (PM2.5), is of specific interest because of its smaller size and its capacity to injure the lower respiratory tract (1,2). This is linked to increased prevalence and exacerbations of chronic respiratory conditions and increased incidence of lung cancer (3). Because of this, the World Health Organization (WHO) has revised its annual mean air quality guideline for PM2.5 and reduced the acceptable range of exposure from 10 to 5 µg/m3 in 2021 (4). And while the global levels of PM2.5 have slightly decreased, the burden of disease associated with PM2.5 has increased, particularly lung cancer in individuals who have never smoked tobacco (NS), emphasizing the need for further study and intervention.
The goal of this article is to review the literature to better understand the relationship of PM2.5 exposure to lung cancer. We will review current literature regarding PM2.5 epidemiology and lung cancer carcinogenesis as it pertains to PM2.5. Then we will conclude with a brief discussion of lung cancer outcomes. We present this article in accordance with the Narrative Review reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1800/rc).

Methods
The following search strategy was employed to focus on PM2.5 epidemiology, mechanisms of oncogenesis, lung cancer, and outcomes (Table 1). We used several terms for our literature search in PubMed and Scopus. Furthermore, we utilized references that we had used for previous research and publications. We used the following terms and strings of terms: PM2.5 epidemiology; PM2.5 AND carcinogenesis; people who have never smoked AND lung cancer carcinogenesis; Lung cancer in people who have never smoked AND outcomes; Lung cancer in people who have never smoked AND surgical outcomes. We limited our selection to those articles that included original research, systematic and other types of review articles, and meta-analyses published between 2004 and 2024. We excluded those studies that were not published in English. Of the 198 articles identified, 45 were identified as relevant to the topic of air pollution epidemiology, carcinogenesis, and outcomes.

PM2.5 epidemiology
Ambient air pollution has emerged as a critical area of investigation due to its ubiquitous nature and association with urbanization and industrial development. The complex mixture of air pollutants comprises two principal categories: gaseous pollutants and PM. Gaseous pollutants, which constitute approximately 90% of airborne contaminants, include ozone (O3), nitrogen dioxide (NO2), volatile organic compounds such as benzene, carbon monoxide (CO), and sulfur dioxide (SO2) (5). PM is classified by aerodynamic diameter, with PM2.5 and PM10 representing the most clinically relevant size fractions. The toxicological effects of these pollutants are primarily determined by particle size distribution and chemical composition, with PM2.5 demonstrating a strong association with adverse health outcomes through cardiovascular and systemic inflammatory pathways (6).
PM2.5 concentrations are highest in areas with significant population density, particularly in major urban centers where air pollution poses the greatest risk. Six of the top ten cities with the highest of PM2.5 concentration are in India (Figure 1A) (7). Still, other factors such as wildfires, agricultural practices, or natural dust, can also contribute and likely explain how some of the relatively unpopulated USA cities have some of the highest concentrations of PM2.5 in the country (Figure 1B) (7). Though some countries have seen a decline in concentrations of PM2.5 between 1980 and 2010, other countries have seen an increase of PM2.5 likely because of industrialization, population growth, and lack of pollution controls (8,9).
Epidemiological evidence linking air pollution to lung cancer, particularly with PM2.5, has accumulated progressively over the past several decades (10-13). Early longitudinal studies in the United States first established associations between long-term exposure to combustion-related PM2.5 and increased lung cancer mortality (14). This study and others contributed to the WHO’s International Agency for Research on Cancer (IARC) classifying outdoor air pollution and its PM components as Group 1 carcinogens (15,16). Subsequent epidemiological investigations have consistently demonstrated positive associations between ambient PM2.5 exposure and lung cancer incidence, with statistical significance maintained after adjustment for smoking status and other established risk factors (17,18). Moreover, Bowe et al. demonstrated that the number of lung cancer cases globally that can be attributed to PM2.5 exposure has increased by 30% since 2007 (19).
The clinical significance of lung cancer in those who have never smoked has also reached unprecedented levels, with approximately 10–15% of United States lung cancer cases now occurring in individuals with no smoking history. This represents a near-doubling from the early 1990s, when NS accounted for approximately 8% of cases, to the early 2010s, when this proportion reached 15% (20). Other studies have shown similar increases in non-tobacco user lung cancer incidence (21,22). The epidemiological burden of lung cancer in NS has become so substantial that, if considered as a distinct malignancy, it would rank among the leading causes of cancer-related mortality worldwide (22).
Furthermore, recent studies have demonstrated that lung cancer incidence in NS shows stronger correlations with poor ambient air quality (23-26). This trend is particularly pronounced among racial minority populations, raising important questions about environmental health disparities and social determinants of cancer risk (23). This demographic shift provides a compelling rationale to examine ambient air pollution as a significant oncogenic exposure in contemporary public health practice.

PM2.5 pathophysiology and mechanisms of carcinogenesis
PM2.5 is unique in that it is small enough to bypass the nasal cavity and upper respiratory tract, allowing it to penetrate deeply into the small airways and alveoli. Exposure to PM2.5 has been associated with upregulation of inflammatory pathways and inflammation of the upper and lower respiratory tract system. Some of these affected pathways are the PI3K/Akt, NF-kB, JAK/STAT, and MAPK signal pathways, which are all implicated is oxidative stress signaling (27-29). These findings supplemented earlier data showing increased reactive oxygen and reactive nitrogen species generation after exposure to PM (30). Furthermore, the increasing oxidative stress caused by PM2.5 has been linked to asthma development and worse exacerbations (31). Interestingly, oxidative and inflammatory effects can persist in lungs despite removal of PM2.5 exposure (32). This may be an explanation as to why, despite decreasing PM2.5 exposure globally, its effects on mortality have persisted. These triggered inflammatory pathways in the lungs contribute to oxidative stress and DNA damage, which can lead to epigenetic changes and carcinogenesis. Such targets include epidermal growth factor receptor (EGFR), which belongs to a group of transmembrane receptors that cause downstream intracellular signaling that promotes cell growth and division (33).
Early research generated data showing cancers in NS had a preponderance towards EGFR mutations, a distinct oncogenic profile from tobacco carcinogenesis, and this observation has been sustained over some years (34,35). Moreover, there have also been many retrospective analyses demonstrating that in NS, there were higher rates of EGFR mutations (33,36). There were also clinical studies observing that NS patients who were treated with the EGFR-targeting small molecules gefitinib or erlotinib exhibited a better response than those who did not smoke (37,38). These data suggested that disease in NS patients may be a unique entity from tobacco-associated lung cancer.
The EGFR pathway establishes a linkage between never-smoking patient oncogenesis and air pollution oncogenesis. A study conducted by Hill suggested that PM2.5 promotes lung cancer by acting on cells that have pre-existing EGFR mutations by increasing the number of interstitial macrophages in the lung that release interleukin-1β (18). This results in a progenitor-like cell state within type 2 alveolar cells, which have mutant EGFR signaling. Wang et al. proposed another mechanism whereby PM2.5 directly promotes tumor progression through activation of EGFR (39). Taken together, these studies provide a potential explanation for the increased incidence of EGFR tumors in NS patients and PM2.5 (40,41).
Osimertinib is a tyrosine kinase inhibitor that was found to have superior outcomes compared to gefitinib and erlotinib, leading it to become the standard of care for EGFR-positive advanced non-small cell lung cancer (NSCLC) (42). Its efficacy in both the adjuvant and neoadjuvant settings has been demonstrated in two trials: ADAURA and NEOADAURA (Table 2). In 2020, the ADAURA trial described the outcomes of stage 1b to 3A EGFR-positive NSCLC when osimertinib was used as adjuvant therapy following surgery and chemotherapy as compared to surgery and chemotherapy alone (43). The 2-year survival was 89% for the treatment group versus 52% for placebo. The NEOADAURA trial investigated the use of osimertinib versus chemotherapy as neoadjuvant therapy for EGFR-positive NSCLC (44). There were 3 treatment arms: osimertinib with chemotherapy, osimertinib therapy alone, and chemotherapy alone. Because many patients were also given osimertinib as adjuvant therapy, the primary endpoint was major pathological response. This study concluded that neoadjuvant osimertinib with or without chemotherapy demonstrated significantly increased major pathological response (26%, 25% vs. 2%), with odds ratios of 19.82 (95.002% CI: 4.60 to 85.33; P<0.0001) and 19.28 (99.9% CI: 1.71 to 217.39; P<0.0001), respectively. While these advances in targeted therapy represent significant contributions to the treatment of EGFR NSCLC, the continued impact of air pollution on lung cancer prevalence underscores the necessity of therapeutic innovation and environmental regulation to decrease overall disease burden.

Outcomes and disparities
Notwithstanding that PM2.5 contributes to the development of a distinct genotype of lung cancer, it can also influence outcomes after treatment of lung cancer. Chandwani et al. sought to explore what environmental and social factors were associated with increased survival after resection of NSCLC in patients who never smoked (45). Significant factors associated with survival were longer distance from the road, the amount of surrounding green space, and PM exposure. Another study by Liu et al. investigated the correlation of PM2.5 exposure and survival of patients after lobectomy and found that an increasing amount of exposure to PM2.5 within 2 months after surgery is associated with an increased risk of death (46). Whitrock et al. also examined post-resection outcomes in relation to air pollution exposure, specifically PM2.5, providing insights into how environmental factors may influence recovery and long-term results following surgical intervention (47). The study concluded that PM2.5 exposure was independently associated with worse post-resection outcomes on univariate and multivariate analysis. Interestingly, PM2.5 exposure was an even more significant predictor of outcome than race or socioeconomic disadvantage. But the study also concluded that there was no difference in PM2.5 exposure between races.
The relationship between air pollution exposure and disparities was explored more thoroughly in a large national study by Jbaily et al. (48). This study showed that areas with higher than average white and native American populations have been consistently exposed to average PM2.5 levels, which are lower than areas with higher than average black, Asian, Hispanic, or Latino populations. They also showed that low-income populations have been consistently exposed to higher average PM2.5 levels than high-income groups from 2004–2016, consistent with another study conducted years later (23). These data suggest that interventions to reduce air pollution, particularly in communities disproportionately exposed, are an opportunity to improve cancer survival even after treatment.
Beyond direct pulmonary effects, PM2.5 may contribute to lung cancer risk through indirect metabolic pathways. Emerging evidence suggests that PM2.5 and its components function as obesogens, promoting weight gain and metabolic dysfunction (49-51). This is particularly relevant given that abdominal obesity has been associated with increased lung cancer risk in meta-analyses (52). This potential indirect carcinogenic pathway through metabolic disruption warrants further investigation, though the relative contribution compared to direct pulmonary mechanisms remains unclear.

Future studies
It is not clear whether the increased global incidence of lung cancer is simply because we are better at diagnosing it, but it is clear that the increased incidence of lung cancer in NS is a public health issue that can be meaningfully linked to air pollution, specifically PM2.5, and future work should explore strategies to continue to mitigate exposure to PM2.5. Because much of the data is correlative, more work is needed to better histologically or biochemically characterize tumors that can be significantly linked to air pollution to further stratify outcomes of those who use smoking tobacco and NS who are exposed to increased levels of PM2.5. This may be a phenomenon to explore when cumulative outdoor exposures to PM2.5 can be more accurately measured, accounting for indoor and outdoor exposure. Perhaps future screening guidelines could even make exceptions for patients who are at an increased ‘environmental risk’ of lung cancer, regardless of smoking status, given that some communities are disproportionately affected by air pollution.

Conclusions
There has been an increased incidence of lung cancer in patients who have never smoked, which can be associated with the increase in air pollution, particularly PM2.5. Furthermore, PM2.5 exposure is associated with worse outcomes after treatment of lung cancer. Because of this linkage between PM2.5 and lung cancer, further research is needed to continue to improve PM2.5 exposure reduction strategies to decrease the associated lung cancers and improve post-treatment outcomes in patients who have never smoked or are at increased exposure to air pollution.

Supplementary
The article’s supplementary files as