Air pollution, driver mutations, and survival in non-small cell lung cancer: insights from a high-altitude Hispanic cohort

Introduction

Lung cancer remains one of the leading causes of cancer-related mortality worldwide, and the impact on individuals who have never smoked is becoming increasingly recognized (1). In fact, lung cancer in never-smokers is the seventh leading cause of cancer-related death worldwide (2). It is estimated that around a quarter of lung cancer cases worldwide occur in individuals who have never smoked (3). While the exact burden in Latin America is not fully quantified, regional cancer registries report nearly 100,000 new lung cancer cases annually, suggesting that lung cancer in never-smokers represents a substantial—and likely under-recognized—proportion of the regional incidence (4-6). These tumors display a distinct demographic and biological profile, arising more often in younger women, presenting predominantly as adenocarcinomas, and carrying a higher frequency of actionable driver mutations such as epidermal growth factor receptor mutations (EGFRm) and anaplastic lymphoma kinase (ALK) rearrangement (7). Most lung cancers in never-smokers are classified as non-small cell lung cancer (NSCLC), highlighting the importance of studying this subgroup where environmental exposures, molecular alterations, and therapeutic opportunities converge (2).

Among non-tobacco determinants, air pollution has emerged as a critical driver of lung carcinogenesis. In 2021, an estimated 19% of lung cancer deaths worldwide were attributable to ambient pollution (8), positioning it as the second leading risk factor for respiratory disease after smoking. Particulate matter (PM_2.5 and PM₁₀) and gaseous pollutants (NO₂, SO₂, O₃, CO) have been linked to increased lung cancer incidence and mortality. Exposure to these pollutants induces chronic airway inflammation, oxidative stress, and impaired DNA repair, while also promoting epigenetic alterations and immune dysregulation (9-14). The pulmonary epithelium, continuously exposed to inhaled substances, is particularly vulnerable to these hazards, which may either initiate malignant transformation or accelerate the progression of pre-existing oncogenic clones. Recent experimental studies reinforce this plausibility: PM_2.5 exposure enhances the oncogenic potential of EGFR-mutant alveolar cells through interleukin-1 beta (IL-1β)-mediated macrophage inflammation, suggesting that air pollutants act not only as initiators but as active promoters of oncogenesis (15-18).

The role of air pollution in lung carcinogenesis is particularly relevant in low- and middle-income countries, where the threshold recommended by the World Health Organization (WHO) for air pollutants is frequently exceeded (19). For instance, over 90% of the population in Latin American cities live in areas with PM_2.5 levels above the WHO’s annual average guideline value of 10 µg/m³ (19), and over 85% live in areas with NO₂ levels above this value (20). In Colombia, median annual concentrations of PM_2.5 range between 8–18 µg/m³, with Bogotá consistently among the most polluted urban centers (21). Notably, the city is located 2,640 meters above sea level, where chronic hypobaric hypoxia increases tidal volume and minute ventilation, facilitating deeper penetration of pollutants into distal airways (22). This unique setting, coupled with marked intraurban variability and strong socioeconomic gradients in exposure, creates a compounded biological and public health risk. While ecological studies in Colombia have linked pollution to cardiorespiratory mortality and chronic obstructive pulmonary disease exacerbations (21,23), its role in lung cancer incidence, molecular characteristics, and prognosis remains largely unexplored.

Despite a growing body of evidence from North America, Europe, and Asia, the relationship between air pollution and driver mutations in lung cancer remains under-characterized in Hispanic populations. This study presents a retrospective cohort analysis of Hispanic patients with NSCLC treated in Bogotá, Colombia, between 2015 and 2022. Using high-resolution geospatial modelling, we estimated long-term exposure to PM_2.5, PM₁₀, NO₂, SO₂, O₃, and CO, and assessed their association with molecular features [EGFR mutations, ALK rearrangements, programmed death-ligand 1 (PD-L1) expression] and overall survival (OS). By integrating environmental and clinical data, our study addresses a significant knowledge gap with direct clinical implications: characterizing pollutant-specific associations with oncogenic drivers and immune biomarkers may inform the use of targeted therapies, optimize patient selection for immunotherapy, and support strategies for early detection and improved survival. At the population level, this knowledge provides one of the first molecular epidemiologic characterizations of pollution-related lung cancer in a high-altitude Latin American setting and offers valuable insights for guiding regulatory policy, reducing exposure, and addressing inequities in access to care. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1334/rc).

Methods

Study design

A retrospective cohort study was conducted to evaluate the association between air pollutants and the presence of EGFRm, ALK alterations, PD-L1 expression, and OS at Fundación Santa Fe de Bogotá, a fourth level of complexity referral center in Bogotá, Colombia between 2015 and 2022. Eligible participants were individuals of at least 18 years of age residing in Bogotá, with biopsy-confirmed NSCLC who underwent basic molecular profiling. Exclusion criteria comprised patients who died during the diagnostic process, and those lacking molecular profiling data. The study was conducted in accordance with national legislation and international ethical standards, adhering to guidelines from the Declaration of Helsinki and its subsequent amendments, the Singapore Statement on Research Integrity, and the Council for International Organizations of Medical Sciences (CIOMS). The study was approved by the Corporate Research Ethics Committee of the Fundación Santa Fe de Bogotá (CCEI-17773-2025, May 13, 2025). No informed consent was required due to the minimal risk classification of this research. The Institutional Ethics Committee authorized a waiver for this document.

Variables and measurements

Clinical and molecular variables collected included: age, sex, smoking status (smoker vs. non-smoker), stage of cancer (I, II, III, IV), family history of lung cancer (yes/no), and treatment received (immunotherapy, chemotherapy, surgery, radiotherapy, and radiosurgery). Molecular data included EGFR mutations, ALK rearrangements, and PD-L1 expressions. EGFR mutations were assessed using the Cobas^® EGFR Mutation Test v2 (Roche Diagnostics) while ALK rearrangements were detected by immunohistochemistry (IHC) using the D5F3 antibody clone. PD-L1 expression was evaluated by 22C3 or SP263 clones.

Environmental pollutant data, including PM_2.5, PM₁₀, NO₂, O₃, CO, and SO₂, were retrieved from the Bogotá Air Quality Monitoring Network (RMCAB; http://rmcab.ambientebogota.gov.co/home/map). Daily and annual averages of each pollutant were computed, utilizing records meeting a minimum temporal representativeness threshold of ≥75% completeness. For each patient, individual pollutant exposure was calculated as the average concentration during the 5 years preceding their NSCLC diagnosis, using inverse distance weighted regression based on daily air quality data linked to the geographic coordinates of residential addresses and monitoring stations. Two distinct circular buffer zones (5 km and 10 km radius) facilitated this spatial interpolation. Exposure levels were analyzed both continuously and categorically, applying the annual WHO 2021 air quality guidelines as categorical cut-off points: 5 µg/m³ for PM_2.5 and 25 µg/m³ for NO₂ (24).

Statistical analysis

Demographic and clinical characteristics of the cohort were summarized with descriptive statistics. Continuous variables were summarized as mean and standard deviation or median and interquartile range (IQR), while categorical variables were reported as absolute and relative frequencies. Logistic regression modeling was employed to assess associations between specific NSCLC alterations (EGFR, ALK, PD-L1) and exposure to air pollutants, adjusting for age, sex, and smoking status. Model performance was validated using the Hosmer-Lemeshow goodness-of-fit test and analysis of residuals. Kaplan-Meier curves were used to visualize OS. Subsequently, Cox proportional hazards models were applied to investigate associations between lung cancer mortality and pollutant exposure (both continuous and categorical), adjusting for sociodemographic (age, sex), clinical (cancer stage, EGFR status, ALK status, PD-L1 expression, family history of lung cancer, and smoking history), and treatment-related covariates. Model adequacy was verified using Schoenfeld residuals and global tests for proportionality assumptions. Selection of final models considered the lowest Akaike Information Criterion, alongside biological plausibility and clinical relevance. Statistical significance was defined as P<0.05. All analyses were conducted using R Studio software, version 4.4.2 (2024-10-31 ucrt).

Results

Descriptive analysis

Table 1 summarizes the baseline characteristics of the 205 patients included in this study. The cohort was predominantly female (60.0%), with a mean age of 66±12.7 years. Most patients presented with advanced-stage disease at diagnosis, with 77.5% classified as stage III or IV. Surgical management, either with palliative or curative intent, was documented in 17% of the cohort, while other therapeutic modalities such as systemic therapy or radiotherapy exhibited greater utilization.

Mean annual exposure to air pollutants during the five years preceding NSCLC diagnosis consistently exceeded the WHO safety thresholds. The annual mean concentration of PM_2.5 was 15.9 µg/m³ [95% confidence interval (CI): 15.4–16.3], PM₁₀ was 32.6 µg/m³ (95% CI: 31.6–33.6), and NO₂ was 28.3 µg/m³ (95% CI: 27.7–28.8). The mean O₃ concentration was 26.7 µg/m³ (95% CI: 26.2–27.3), while CO and SO₂ registered mean values of 76.3 µg/m³ (95% CI: 74.5–78.1) and 4.63 µg/m³ (95% CI: 4.14–5.12), respectively. Figure 1 illustrates the spatial distribution of air pollutant concentrations across Bogotá, highlighting the variability in exposure based on patients’ circular buffers.

Figure 1 Spatial distribution of individual exposure levels to ambient air pollutants across Bogotá, Colombia. Each panel represents the estimated concentration (µg/m³) at the domicile of patients with non-small cell lung cancer. (A) PM_2.5; (B) PM₁₀; (C) NO₂; (D) O₃; (E) SO₂; and (F) CO.

Regarding molecular alterations, 57 patients (27.9%) carried EGFR mutations. The most frequent was exon 19 deletion (n=30, 58.8%), followed by the L858R mutation (n=14, 27.5%). Exon 20 insertions were identified in 5 patients (9.8%), and less common sensitizing mutations, such as L861Q and G719X, were found in 1 patient each (2.0%). ALK rearrangements were detected in 25 patients (12.2%) by IHC with the D5F3 clone. PD-L1 expression with tumor proportion score (TPS) ≥1% was observed in 96 patients (46.8%), while TPS ≥50% was detected in 11 patients (5.4%).

Logistic regression analysis

Table 2 shows the results of logistic regression analysis examining the effects of EGFR, ALK, and PD-L1 mutation type according to exposure to air pollutants. Higher exposure to particulate matter was significantly associated with the presence of EGFR mutations. Each 10 µg/m³ increase in PM_2.5 was associated with an odds ratio (OR) of 2.49 (95% CI: 1.11–6.41), and each 10 µg/m³ increase in PM₁₀ with an OR of 1.54 (95% CI: 1.05–2.34).

Air pollutant exposures were not associated with ALK rearrangements, except for CO exposure. Among the biomarkers, PD-L1 expression was significantly associated with NO₂ exposure. Each 10 µg/m³ increase in NO₂ corresponded to an OR of 1.83 (95% CI: 1.33–2.65; P<0.001). No other pollutant showed significant associations with PD-L1 expression after adjustment (Table 2).

Most logistic regression models demonstrated adequate fit, with no major deviations between predicted and observed outcomes. The only exception was the EGFR model including PM₁₀, which showed a lack of fit (Hosmer-Lemeshow χ²=21.17, P=0.007), suggesting potential model misspecification. For all other models, Hosmer-Lemeshow P values exceeded 0.05, supporting their robustness in assessing biomarker-pollution associations.

Survival analysis

The median OS for the cohort was 31 months (95% CI: 27.6–37.2). Survival rates at 1, 3, and 5 years were 72.1%, 43.0%, and 29.0%, respectively. Kaplan-Meier curves are presented in Figure 2.

Figure 2 Kaplan-Meier of patients with non-small cell lung cancer from 2015 to 2022 in Bogotá, Colombia.

Cox proportional hazards analysis

Table 3 shows a full summary of results of Cox proportional hazard analysis. In adjusted models, higher exposure to PM_2.5 and SO₂ emerged as significant predictors of increased mortality risk. Each 10 µg/m³ increase in PM_2.5 was associated with a hazard ratio (HR) of 1.72 (95% CI: 1.04–2.84; P=0.04), while each 10 µg/m³ increase in SO₂ corresponded to an HR of 1.69 (95% CI: 1.07–2.68; P=0.03). By contrast, PM₁₀, NO₂, O₃, and CO did not show significant associations with mortality. Fully adjusted Cox proportional hazards ratios, including all confounders considered in the final models, are detailed in Table S1.

EGFR mutations and ALK rearrangements were both associated with reduced mortality (HR 0.40–0.46; P<0.05). PD-L1 expression displayed borderline significance in certain models (Table 3).

Discussion

Our study, conducted in a high-altitude urban cohort of Hispanic patients with NSCLC, shows that ambient air pollution is associated with both disease incidence and tumor biology and survival. At the clinical level, pollutant-specific associations with oncogenic drivers such as EGFR and immune biomarkers such as PD-L1 have direct implications for precision oncology: they may refine the selection of patients for targeted therapies, enhance stratification for immunotherapy, and support the development of screening strategies aimed at earlier diagnosis and improved survival (25-28). At the public health level, understanding how environmental exposures shape tumor biology could guide policies on pollution control, promote more equitable access to care, and reduce the economic burden of advanced-stage disease in resource-constrained settings.

The most consistent molecular associations were observed between particulate matter and EGFR mutations. Patients exposed to higher levels of PM_2.5 had nearly a 2.5-fold increased probability of harboring EGFR-mutant tumors per 10 µg/m³ increment (OR: 2.49, 95% CI: 1.11–6.41), while PM₁₀ conferred a 1.5-fold increase (OR: 1.54, 95% CI: 1.05–2.34). This suggests that fine and coarse particulates may act as selective pressures for EGFR-driven oncogenesis, either by promoting expansion of pre-existing mutant clones or by inducing genomic alterations (29). Previous epidemiologic research has shown that increments of 10 µg/m³ in PM_2.5 are associated with 15–27% increases in lung cancer mortality (30), supporting the epidemiological relevance of our findings. Mechanistically, particulate matter induces chronic airway inflammation, oxidative stress, and DNA damage, while impairing DNA repair pathways and altering epigenetic regulation (9-14). Recent experimental data confirm that macrophages exposed to PM_2.5 enhance the oncogenic fitness of EGFR-mutant alveolar cells via IL-1β-mediated inflammation (15-18). Beyond this macrophage-driven effect, PM_2.5 induces reactive oxygen species that can indirectly activate EGFR, while chronic particulate matter-induced inflammation promotes nuclear factor kappa B (NF-κB) signaling and the release of proinflammatory cytokines [including IL-1β, IL-6, and tumor necrosis factor alpha (TNF-α)], further potentiating EGFR signaling; in parallel, activation of the aryl hydrocarbon receptor (AhR) may stimulate EGFR through both genomic mechanisms, via transcriptional regulation of EGFR-related genes, and non-genomic mechanisms involving Src-dependent tyrosine kinase signaling, collectively enhancing EGFR-Src crosstalk, tumor proliferation, metastatic potential, and resistance to EGFR-targeted therapies under sustained PM_2.5 exposure (31). These results suggest that particulate matter is not a passive initiator but an active promoter of EGFR-driven tumorigenesis.

In contrast, the associations between gaseous pollutants and tumor biology followed different patterns. NO₂ exposure was significantly correlated with increased PD-L1 expression, suggesting that chronic traffic-related pollution may contribute to immune escape mechanisms in NSCLC (32,33). Elevated NO₂ levels trigger oxidative stress and airway inflammation, disrupt T-cell functionality, and enhance expression of checkpoint molecules, which could partly explain our observations (32-35). This finding is consistent with the hypothesis that air pollution can modulate the tumor immune microenvironment, potentially influencing response to immunotherapy (34,35). While ALK rearrangements showed no robust associations, we did observe a signal with CO exposure. Given CO’s capacity to generate cellular hypoxia and oxidative imbalance (36,37), this association deserves further validation in larger cohorts.

The survival analysis further highlighted the prognostic impact of environmental exposures. Long-term exposure to PM_2.5 increased the risk of death by 72% per 10 µg/m³ increment, while SO₂ exposure increased mortality risk by 69%. These magnitudes surpass those reported in other regions, where HRs for PM_2.5 typically range between 1.14 and 1.30 (29). PM_2.5 is a potent inducer of chronic inflammation, angiogenesis, and immune exhaustion, which may accelerate disease progression even after diagnosis (29). SO₂, often linked to fossil fuel combustion, generates reactive oxygen species that promote cellular injury and compromise repair mechanisms, yet its role in lung cancer prognosis has been less explored (38,39). Conversely, the presence of EGFR or ALK alterations was significantly associated with reduced mortality (HR 0.40–0.46; P<0.05), aligning with prior evidence that patients harboring targetable driver mutations benefit from improved outcomes when effective therapies are available. PD-L1 expression demonstrated a borderline effect in some models (Table 3), which may reflect heterogeneity in testing or treatment access, and highlights the complex interplay between environmental exposures and tumor immune profiles. These results underscore that pollutants act not only as carcinogens but also as modifiers of survival, while molecular alterations can mitigate prognosis when actionable.

From a public health perspective, the descriptive profile of the cohort provides important context: the majority were women, with a mean age of 66 years, and almost 80% presented with advanced stages (III–IV). This distribution highlights the lack of lung cancer screening programs in Colombia and other Latin American countries, where late presentation remains the norm (5,40,41). Molecular profiling showed EGFR mutations in nearly one-quarter of patients, ALK rearrangements in 12.2%, and PD-L1 expression in over 40%—prevalences aligned with data from never-smokers and Hispanic or Asian cohorts. Importantly, annual exposures to PM_2.5 (15.9 µg/m³), PM₁₀ (32.6 µg/m³), and NO₂ (28.3 µg/m³) exceeded WHO thresholds, positioning Bogotá as a real-world laboratory where environmental and biological risks converge. More broadly, most urban populations across Latin America are chronically exposed to pollutant concentrations that surpass WHO recommendations (42-45), underscoring that our findings are not isolated to Bogotá but rather reflect a wider environmental reality that may have implications for cancer control in the region.

These patterns must also be interpreted in the context of Bogotá’s unique environmental conditions. At 2,640 meters above sea level, residents live under chronic hypobaric hypoxia, which induces increased tidal volume and ventilation (22). This physiological adaptation facilitates deeper penetration of inhaled particles into distal airways, effectively amplifying the biologically active dose of pollutants compared with equivalent concentrations at sea level (22). The meteorological conditions at high altitudes can also affect the dispersion and deposition of pollutants, thereby uniquely impacting air quality (46). Bogotá is notable for having the greatest intraurban variability in PM_2.5 among major Colombian cities (21), a feature that, combined with its altitude, offers a unique opportunity to explore the health effects of air pollution exposure with greater resolution. This combination enhances both exposure to heterogeneity and biological susceptibility. Together, these contextual factors may explain why the HRs and ORs observed in our cohort were higher than those reported in North America, Europe, or Asia, underscoring the importance of studying Latin American populations independently rather than extrapolating data from other regions.

An integrative view of our findings suggests a dual-axis model in which air pollutants both predispose to specific oncogenic events and independently shape survival outcomes. Higher exposures to PM_2.5 and PM₁₀ were associated with increased prevalence of EGFR mutations, yet EGFR positivity itself correlated with improved OS, likely reflecting access to effective EGFR-targeted therapies. This paradox illustrates how pollution may increase the burden of EGFR-driven tumors in the population, while advances in precision oncology partially offset their lethality at the individual level (47-49). Conversely, pollutants such as SO₂ were associated exclusively with worse survival, independent of mutation status, pointing toward mechanisms of disease acceleration unrelated to genomic drivers. The association of NO₂ with elevated PD-L1 expression also raises questions about how chronic inflammation and immune checkpoint upregulation may influence both tumorigenesis and therapeutic responsiveness. Thus, our results highlight a layered relationship where environmental exposures simultaneously determine the likelihood of certain driver events and modulate the natural history of disease after diagnosis. Beyond the clinical implications, this evidence reinforces the need for public health strategies that integrate environmental risk into cancer control policies, with the dual aim of reducing pollutant exposure and improving equity in access to early detection and advanced therapies. Future research should continue to investigate these relationships, incorporating multi-pollutant exposure frameworks and indoor air pollution assessments to more comprehensively characterize the impact of ambient air pollution on lung cancer risk and progression.

Several limitations should be acknowledged. The retrospective design restricts causal inference and may introduce biases. Individual-level exposures such as occupational risks, indoor pollutants, and residential mobility throughout the study period were not captured in the clinical records, which could lead to exposure misclassification despite the use of geospatial modeling. The retrospective nature of the study did not allow us to collect information on built environment data. Moreover, the representativeness of our cohort warrants consideration: as a quaternary referral center in Bogotá, the Fundación Santa Fe de Bogotá receives patients with relatively better access to diagnostic and therapeutic resources, which may not fully reflect the experience of the broader Colombian population. At a regional level, socioeconomic and healthcare access disparities across Latin America further limit generalizability. Despite these limitations, this study represents one of the first in Latin America to integrate environmental exposure, molecular alterations, and survival outcomes in NSCLC.

Conclusions

Our study provides one of the first integrative analyses of air pollution and lung cancer biology in a Latin American, high-altitude population. We showed that ambient pollutants are not only carcinogens but also determinants of tumor evolution and patient survival. PM_2.5 and PM₁₀ were strongly associated with the presence of EGFR mutations, NO₂ with PD-L1 expression, and SO₂ with worse OS, outlining a pollutant-specific molecular and prognostic signature. These associations suggest a dual mechanism whereby pollution simultaneously increases the likelihood of oncogenic events and accelerates disease progression, while actionable mutations such as EGFR and ALK can mitigate prognosis when targeted therapies are accessible. The unique setting of Bogotá—marked by chronic hypoxia, intraurban heterogeneity, and exposure above WHO thresholds—amplifies both risk and clinical impact, reinforcing the need to study Hispanic populations independently. Despite inherent limitations, our findings highlight the urgency of integrating environmental exposures into lung cancer risk stratification, prognostic modeling, and public health policy, and provide a foundation for multicenter research aimed at reducing the burden of pollution-related lung cancer in underrepresented regions.

Acknowledgments

The authors acknowledge the institutional support of the Fundación Santa Fe de Bogotá. We extend our appreciation to the Department of Pathology and the Cancer Institute for their collaboration and access to essential clinical and molecular records. We further acknowledge the Universidad de los Andes, Faculty of Medicine, for its academic guidance and support during the development of this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1334/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1334/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1334/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1334/coif). L.E.P. declared that currently, I am a stockholder for OxLER and I receive profits from this company; similarly, it has contracts with Johnson & Johnson, AstraZeneca, and Roche in digital consulting, process consulting, and AI development. A.F.C. received that, as previously described, I have received grants from several companies (all listed specifically in this form) for developing an investigation, however, not related to the current project. Similarly, I have consultant roles and have been a speaker for the companies I previously described, and have received earnings from these entities. I also belong to advisory boards both for industries as well as for international oncologic societies. Several different entities have provided support for attending international meetings and congresses. B.W. reported that, as previously described, I have received grants from BMS and AstraZeneca for developing an investigation, however, not related to the current project. Similarly, I have consultant roles with Johnson and Johnson, AstraZeneca, Roche, and Pfizer. I have been a speaker for AbbVie, Johnson & Johnson, AstraZeneca, Roche, and Bayer. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with national legislation and international ethical standards, adhering to guidelines from the Declaration of Helsinki and its subsequent amendments, the Singapore Statement on Research Integrity, and the Council for International Organizations of Medical Sciences (CIOMS). The study was approved by the Corporate Research Ethics Committee of the Fundación Santa Fe de Bogotá (CCEI-17773-2025, May 13, 2025). No informed consent was required due to the minimal risk classification of this research. The Institutional Ethics Committee authorized a waiver for this document.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Berg CD, Schiller JH, Boffetta P, et al. Air Pollution and Lung Cancer: A Review by International Association for the Study of Lung Cancer Early Detection and Screening Committee. J Thorac Oncol 2023;18:1277-89. [Crossref] [PubMed]
2. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers--a different disease. Nat Rev Cancer 2007;7:778-90. [Crossref] [PubMed]
3. Couraud S, Zalcman G, Milleron B, et al. Lung cancer in never smokers--A review. Eur J Cancer 2012;48:1299-311. [Crossref] [PubMed]
4. Piñeros M, Laversanne M, Barrios E, et al. An updated profile of the cancer burden, patterns and trends in Latin America and the Caribbean. Lancet Reg Health Am 2022;13:100294.
5. Raez LE, Cardona AF, Santos ES, et al. The burden of lung cancer in Latin-America and challenges in the access to genomic profiling, immunotherapy and targeted treatments. Lung Cancer 2018;119:7-13. [Crossref] [PubMed]
6. LoPiccolo J, Gusev A, Christiani DC, et al. Lung cancer in patients who have never smoked - an emerging disease. Nat Rev Clin Oncol 2024;21:121-46. [Crossref] [PubMed]
7. Moorthi S, Paguirigan A, Itagi P, et al. The genomic landscape of lung cancer in never-smokers from the Women’s Health Initiative. JCI Insight 2024;9:e174643. [Crossref] [PubMed]
8. Health Effects Institute. Health Impacts of Air Pollution. 2024. Available online: https://www.stateofglobalair.org/hap
9. Li J, Song H, Luo T, et al. Exposure to O(3) and NO(2) on the interfacial chemistry of the pulmonary surfactant and the mechanism of lung oxidative damage. Chemosphere 2024;362:142669. [Crossref] [PubMed]
10. Quezada-Maldonado EM, Sánchez-Pérez Y, Chirino YI, et al. Airborne particulate matter induces oxidative damage, DNA adduct formation and alterations in DNA repair pathways. Environ Pollut 2021;287:117313. [Crossref] [PubMed]
11. Barbier E, Carpentier J, Simonin O, et al. Oxidative stress and inflammation induced by air pollution-derived PM(2.5) persist in the lungs of mice after cessation of their sub-chronic exposure. Environ Int 2023;181:108248. [Crossref] [PubMed]
12. Liu B, Han Y, Ye Y, et al. Atmospheric fine particulate matter (PM(2.5)) induces pulmonary fibrosis by regulating different cell fates via autophagy. Sci Total Environ 2024;923:171396. [Crossref] [PubMed]
13. Chang EM, Chao CC, Wang MT, et al. PM2.5 promotes pulmonary fibrosis by mitochondrial dysfunction. Environ Toxicol 2023;38:1905-13. [Crossref] [PubMed]
14. Kayalar Ö, Rajabi H, Konyalilar N, et al. Impact of particulate air pollution on airway injury and epithelial plasticity; underlying mechanisms. Front Immunol 2024;15:1324552. [Crossref] [PubMed]
15. Huang Y, Zhu M, Ji M, et al. Air Pollution, Genetic Factors, and the Risk of Lung Cancer: A Prospective Study in the UK Biobank. Am J Respir Crit Care Med 2021;204:817-25. [Crossref] [PubMed]
16. Ramamoorthy T, Nath A, Singh S, et al. Assessing the Global Impact of Ambient Air Pollution on Cancer Incidence and Mortality: A Comprehensive Meta-Analysis. JCO Glob Oncol 2024;10:e2300427. [Crossref] [PubMed]
17. Hvidtfeldt UA, Severi G, Andersen ZJ, et al. Long-term low-level ambient air pollution exposure and risk of lung cancer - A pooled analysis of 7 European cohorts. Environ Int 2021;146:106249. [Crossref] [PubMed]
18. Wang M, Kim RY, Kohonen-Corish MRJ, et al. Particulate matter air pollution as a cause of lung cancer: epidemiological and experimental evidence. Br J Cancer 2025;132:986-96. [Crossref] [PubMed]
19. Gouveia N, Kephart JL, Dronova I, et al. Ambient fine particulate matter in Latin American cities: Levels, population exposure, and associated urban factors. Sci Total Environ 2021;772:145035. [Crossref] [PubMed]
20. Kephart JL, Gouveia N, Rodríguez DA, et al. Ambient nitrogen dioxide in 47 187 neighbourhoods across 326 cities in eight Latin American countries: population exposures and associations with urban features. Lancet Planet Health 2023;7:e976-84. [Crossref] [PubMed]
21. Marín D, Herrera V, Piñeros-Jiménez JG, et al. Long-term exposure to PM2.5 and cardiorespiratory mortality: an ecological small-area study in five cities in Colombia. Cad Saude Publica 2025;41:e00071024. [Crossref] [PubMed]
22. Li Y, Frandsen KM, Guo W, et al. Impact of altitude on the dosage of indoor particulates entering an individual’s small airways. J Hazard Mater 2024;468:133856. [Crossref] [PubMed]
23. Herrera Lopez AB, Torres-Duque CA, Casas Herrera A, et al. Frequency of Exacerbations of Chronic Obstructive Pulmonary Disease Associated with the Long-Term Exposure to Air Pollution in the AIREPOC Cohort. Int J Chron Obstruct Pulmon Dis 2025;20:425-35. [Crossref] [PubMed]
24. World Health Organization. WHO global air quality guidelines: particulate matter (PM2.5 and PM10), ozone, nitrogen dioxide, sulfur dioxide and carbon monoxide. Geneva: World Health Organization; 2021.
25. Peng L, Li H, Yan W, et al. Integrative profiling of lung cancer biomarkers EGFR, ALK, KRAS, and PD-1 with emphasis on nanomaterials-assisted immunomodulation and targeted therapy. Front Immunol 2025;16:1649445. [Crossref] [PubMed]
26. Zhao Y, He Y, Wang W, et al. Efficacy and safety of immune checkpoint inhibitors for individuals with advanced EGFR-mutated non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitors: a systematic review, meta-analysis, and network meta-analysis. Lancet Oncol 2024;25:1347-56. [Crossref] [PubMed]
27. Roulleaux Dugage M, Albarrán-Artahona V, Laguna JC, et al. Biomarkers of response to immunotherapy in early stage non-small cell lung cancer. Eur J Cancer 2023;184:179-96. [Crossref] [PubMed]
28. Sholl LM, Awad M, Basu Roy U, et al. Programmed Death Ligand-1 and Tumor Mutation Burden Testing of Patients With Lung Cancer for Selection of Immune Checkpoint Inhibitor Therapies: Guideline From the College of American Pathologists, Association for Molecular Pathology, International Association for the Study of Lung Cancer, Pulmonary Pathology Society, and LUNGevity Foundation. Arch Pathol Lab Med 2024;148:757-74. [Crossref] [PubMed]
29. Hill W, Lim EL, Weeden CE, et al. Lung adenocarcinoma promotion by air pollutants. Nature 2023;616:159-67. [Crossref] [PubMed]
30. Turner MC, Andersen ZJ, Baccarelli A, et al. Outdoor air pollution and cancer: An overview of the current evidence and public health recommendations. CA Cancer J Clin 2020; [Crossref]
31. Chen CY, Huang KY, Chen CC, et al. The role of PM2.5 exposure in lung cancer: mechanisms, genetic factors, and clinical implications. EMBO Mol Med 2025;17:31-40. [Crossref] [PubMed]
32. Glencross DA, Ho TR, Camiña N, et al. Air pollution and its effects on the immune system. Free Radic Biol Med 2020;151:56-68. [Crossref] [PubMed]
33. Cattani-Cavalieri I, Ostrom KF, Margolis J, et al. Air pollution and diseases: signaling, G protein-coupled and Toll like receptors. Pharmacol Ther 2025;275:108920. [Crossref] [PubMed]
34. Narayanapillai SC, Han YH, Song JM, et al. Modulation of the PD-1/PD-L1 immune checkpoint axis during inflammation-associated lung tumorigenesis. Carcinogenesis 2020;41:1518-28. [Crossref] [PubMed]
35. Liu B, Jiang M, Wu Y, et al. Impact of air pollution on the progress-free survival of non-small cell lung cancer patients with anti-PD-1/PD-L1 immunotherapy: A cohort study. Environ Pollut 2025;368:125683. [Crossref] [PubMed]
36. Rose JJ, Wang L, Xu Q, et al. Carbon Monoxide Poisoning: Pathogenesis, Management, and Future Directions of Therapy. Am J Respir Crit Care Med 2017;195:596-606. [Crossref] [PubMed]
37. Chenoweth JA, Albertson TE, Greer MR. Carbon Monoxide Poisoning. Crit Care Clin 2021;37:657-72. [Crossref] [PubMed]
38. Qin G, Meng Z. Effects of sulfur dioxide derivatives on expression of oncogenes and tumor suppressor genes in human bronchial epithelial cells. Food Chem Toxicol 2009;47:734-44. [Crossref] [PubMed]
39. Tseng CY, Huang YC, Su SY, et al. Cell type specificity of female lung cancer associated with sulfur dioxide from air pollutants in Taiwan: an ecological study. BMC Public Health 2012;12:4. [Crossref] [PubMed]
40. Mosquera I, Barajas CB, Theriault H, et al. Assessment of barriers to cancer screening and interventions implemented to overcome these barriers in 27 Latin American and Caribbean countries. Int J Cancer 2024;155:719-30. [Crossref] [PubMed]
41. Global, regional, and national burden of respiratory tract cancers and associated risk factors from 1990 to 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Respir Med 2021;9:1030-49.
42. Husaini DC, Reneau K, Balam D. Air pollution and public health in Latin America and the Caribbean (LAC): a systematic review with meta-analysis. Beni Suef Univ J Basic Appl Sci 2022;11:122. [Crossref] [PubMed]
43. Cortes S. Air pollution and environmental epidemiological evidence in Chile: alerts for decision-makers and citizens. J Epidemiol Community Health 2023;jech-2023-220594.
44. Pereira Barboza E, Nieuwenhuijsen M, Ambròs A, et al. The impact of urban environmental exposures on health: An assessment of the attributable mortality burden in Sao Paulo city, Brazil. Sci Total Environ 2022;831:154836. [Crossref] [PubMed]
45. Ribeiro AG, Downward GS, Freitas CU, et al. Incidence and mortality for respiratory cancer and traffic-related air pollution in São Paulo, Brazil. Environ Res 2019;170:243-51. [Crossref] [PubMed]
46. Ning Z, Ma Y, He S, et al. High altitude air pollution and respiratory disease: Evaluating compounded exposure events and interactions. Ecotoxicol Environ Saf 2024;285:117046. [Crossref] [PubMed]
47. Singal G, Miller PG, Agarwala V, et al. Association of Patient Characteristics and Tumor Genomics With Clinical Outcomes Among Patients With Non-Small Cell Lung Cancer Using a Clinicogenomic Database. JAMA 2019;321:1391-9. [Crossref] [PubMed]
48. Jiang Y, Lin Y, Fu W, et al. The impact of adjuvant EGFR-TKIs and 14-gene molecular assay on stage I non-small cell lung cancer with sensitive EGFR mutations. EClinicalMedicine 2023;64:102205. [Crossref] [PubMed]
49. Saw SPL, Zhou S, Chen J, et al. Association of Clinicopathologic and Molecular Tumor Features With Recurrence in Resected Early-Stage Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung Cancer. JAMA Netw Open 2021;4:e2131892. [Crossref] [PubMed]