# Sex-Specific Vulnerabilities in Lung Adenocarcinoma Among Non-Smoking Women: A Conceptual Review of Multisystem Pathways and Preventive Implications

## TL;DR

This paper explores why non-smoking women are more vulnerable to lung adenocarcinoma by examining biological and psychosocial factors beyond pollution exposure.

## Contribution

It introduces a multisystem framework linking sensory processing, hormones, and stress to explain sex-specific cancer risks in non-smoking women.

## Key findings

- Female-specific biological and psychosocial factors amplify lung cancer risk beyond exposure alone.
- A multisystem model connects chemosensory, hormonal, and stress pathways to tumor-promoting inflammation and signaling.
- Estrogen-EGFR crosstalk and HPA axis dysregulation are key modulators in lung carcinogenesis among non-smoking women.

## Abstract

Lung adenocarcinoma in women who have never smoked is increasingly recognized as a distinct disease entity. Although air pollution is an established risk factor, differences in susceptibility between women and men suggest that additional biological mechanisms are involved. In this conceptual review, we propose a multisystem framework in which sensory processing, hormonal regulation, and stress-related neuroendocrine pathways interact to amplify inflammation, immune dysregulation, and tumor-promoting signaling in the lung. By integrating evidence across these domains, we highlight how female-specific biological and psychosocial factors may contribute to lung cancer development beyond exposure alone. This perspective provides a foundation for mechanism-informed prevention strategies and public health approaches tailored to non-smoking women.

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.