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 (scRNA-seq) and bulk sequencing data, we identified cell subpopulations associated with smoking and non-smoking patients. Downstream transcriptomic analyses were then performed to reveal differences in cell function and 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 CXCL10+ macrophages may be involved in their 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 their tumor formation. Moreover, the decreased anti-tumor cytotoxicity could 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 immunotherapy strategies.
Zhao et al. (Wed,) studied this question.