Integrating bulk and single-cell sequencing reveals cellular heterogeneity between lung adenocarcinoma in smokers and never-smokers

Lung cancer in smokers (LCIS) and lung cancer in never-smokers (LCINS) are different entities with distinct molecular features. However, their cellular heterogeneity still requires further investigation. Through an integrated analysis of single-cell RNA sequencing and bulk sequencing data, we identified cell subpopulations associated with smoking and non-smoking patients. Subsequent transcriptomic analyses were performed to elucidate differences in cellular functions and the tumor microenvironment. We observed that smoking-associated cancer cells exhibited a higher degree of aggressiveness, which may correlate with an adverse prognosis in smoking patients. Additionally, immunosuppressive <i>CXCL10</i> ⁺ macrophages may contribute to tumorigenesis in smokers, and the immunoregulatory LGALS9-HAVCR2 axis could be a potential immunotherapeutic target. In non-smokers, the inflammatory microenvironment may be involved in tumor development. Moreover, the reduced anti-tumor cytotoxicity may be associated with their suboptimal immunotherapeutic response. Our study uncovered differences in oncogenic and immune escape mechanisms between LCIS and LCINS patients and suggests potential immunotherapeutic strategies.