Disentangling Links Between Lung Cancer and Infectious Pneumonia via Real-World Data and Integrative Genomics

Lung cancer (LC) patients frequently develop infectious pneumonia, often leading to suspension of anticancer therapy, yet the impact of LC on pneumonia progression remains unclear. This study employed a multidimensional approach to investigate whether LC constitutes a critical factor contributing to pulmonary infection onset and adverse short-term outcomes. Data from two intensive care unit databases were analyzed to assess the association between LC and pneumonia incidence and prognosis from a real-world perspective, with Mendelian randomization (MR) applied to validate causality. Additionally, post-GWAS analyses were conducted to explore comorbidity interaction patterns and potential shared therapeutic targets. Cross-sectional and cohort analyses identified LC as an independent risk factor for infectious pneumonia development and 28-day mortality, findings corroborated by sensitivity analyses across multiple models and datasets. Meta-analysis of MR results demonstrated causal relationships between genetically predicted LC and both pneumonia risk (OR = 1.103, 95% CI: 1.031–1.181, p = 0.004) and short-term mortality (OR = 1.219, 95% CI: 1.100–1.350, p < 0.001), with consistency across histological subtypes. After adjustment for comorbidities including chronic obstructive pulmonary disease (COPD), LC retained independent effects, while a strong LC–COPD genetic correlation was observed. Subgroup and mediation analyses revealed a two-way interplay between LC and COPD in driving pneumonia progression. Drug-target analyses suggested that modulation of the complement and coagulation cascades may benefit pneumonia patients with comorbid LC or COPD, highlighting CFB, SERPINA1, and SERPING1 as key candidates and pointing to monocyte-centered pathways as promising therapeutic directions. These findings indicate that infection-related pulmonary inflammation in LC patients may be partly tumor-driven, challenging routine cessation of anticancer therapy and underscoring the need for comorbidity-oriented treatment strategies.