The role of PM2.5 exposure in lung cancer: mechanisms, genetic factors, and clinical implications

Abstract

Lung cancer is one of the most critical global health threats, as the second most common cancer and leading cause of cancer deaths globally. While smoking is the primary risk factor, an increasing number of cases occur in nonsmokers, with lung cancer in nonsmokers (LCNS) now recognized as the fifth leading cause of cancer mortality worldwide. Recent evidence identifies air pollution, particularly fine particulate matter (PM2.5), as a significant risk factor in LCNS. PM2.5 can increase oxidative stress and inflammation, induce genetic alterations and activation of oncogenes (including the epidermal growth factor receptor, EGFR), and contribute to lung cancer progression. This review summarizes the current understanding of how exposure to PM2.5 induces lung carcinogenesis and accelerates lung cancer development. It underscores the importance of prevention and early detection while calling for targeted therapies to combat the detrimental effects of air pollution. An integrated approach that combines research, public health policy, and clinical practice is essential to reduce the lung cancer burden and improve outcomes for those affected by PM2.5 exposurrre.

Keywords: DNA Damage; EGFR; Inflammation; Lung Cancer; PM2.5.

Figure 1. Lung cancer in smokers and nonsmokers among the top 10 leading causes of cancer death worldwide in 2020.

Lung cancer in smokers (S) and nonsmokers (NS), highlighted in red, represents the first and fifth leading causes of cancer death, respectively. Modified from (LoPiccolo et al, 2024).

Figure 2. PM2.5 may be involved in the initiation, selection, and/or promotion of lung cancer in nonsmokers.

Schematic showing the molecular pathways by which PM2.5 contributes to lung carcinogenesis. It contributes to lung cancer initiation by inducing inflammation, oxidative stress, and DNA damage. PM2.5 also selects for preexisting EGFR mutations, increasing EGFR activation (wild type and mutant), which leads to oncogene activation, tumor progression, cancer metastasis, drug resistance, and ultimately, lung cancer development. The role of inflammatory cytokines, such as IL-1 and IL-18, is highlighted, indicating their contribution to chronic inflammation and the promotion of tumor progression. In addition, AhR activation by PM2.5 influences EGFR signaling, promoting cancer cell proliferation and resistance to EGFR–TKIs through Src signaling activation.