Coordinated microbial-inflammatory associations in never-smoking lung cancer

While smoking is the leading cause of lung cancer, the increasing incidence among never-smokers is a growing concern, highlighting non-tobacco-related mechanisms of carcinogenesis. Emerging evidence suggests that respiratory microbial dysbiosis and associated inflammatory responses may contribute to lung tumorigenesis. We previously showed that elevated abundances of Selenomonas, Streptococcus, and Veillonella are correlated with lung cancer independent of smoking history. Here, we examine whether circulating microbial and inflammatory profiles are linked to lung cancer in never-smokers.

Circulating bacterial DNA representing the three genera was quantified by droplet digital PCR, and seven systemic inflammatory cytokines were measured by ELISA in plasma of 56 ever-smoker lung cancer patients, 56 never-smoker lung cancer patients, and 78 healthy controls. Integrative statistical modeling was performed to evaluate relationships among bacterial DNA burden, inflammatory activation, smoking history, and cancer status.

Plasma DNA levels of Selenomonas, Streptococcus, and Veillonella, together with IL-6, TNF-α, IL-1β, IL-8, and IL-17A, were elevated in lung cancer patients compared with controls (all p < 0.05). No significant differences were observed between smoking and never-smoking lung cancer patients for bacterial DNA levels, IL-6, TNF-α, or IL-17A (all > 0.05), whereas modest but statistically significant differences were observed for IL-8 (P = 0.036) and IL-1β (P = 0.048). Bacterial DNA burden was correlated with systemic inflammatory cytokine activation independent of smoking history (all p < 0.05).

A smoking-independent microbial-inflammatory signature is associated with lung cancer and provides a foundation for future studies evaluating its biological significance and clinical utility for diagnosis and management.