Sex-Specific Vulnerabilities in Lung Adenocarcinoma Among Non-Smoking Women: A Conceptual Review of Multisystem...

Background: Lung adenocarcinoma in non-smoking women represents a distinct clinical entity that cannot be fully explained by traditional exposure-centered carcinogenic models. Although ambient air pollution is a recognized risk factor, sex-specific vulnerability suggests the involvement of additional biological modulators shaping inflammatory, immune, and proliferative responses. Main body: In this conceptual review, we integrate epidemiological, experimental, and mechanistic evidence to propose a multisystem framework of lung carcinogenesis in non-smoking women. We delineate a central carcinogenic spine encompassing lung epithelial injury, chronic inflammation, growth factor signaling activation-particularly epidermal growth factor receptor (EGFR) pathways-and tumor microenvironment remodeling. Within this framework, three interacting domains function as biological modulators that amplify carcinogenic processes: chemosensory-neural-immune modulation, hormonal-endocrine signaling including estrogen-EGFR crosstalk, and psychosocial stress-hypothalamic-pituitary-adrenal (HPA) axis dysregulation. These domains converge through feedback mechanisms that reinforce systemic dysregulation and tumor-promoting microenvironments. Implications: This integrative model provides a biologically grounded perspective on female-specific vulnerability to lung adenocarcinoma and informs precision prevention, risk stratification, and ESG-informed public health strategies beyond conventional exposure reduction.