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

Abstract

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 CXCL10⁺ 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.

Keywords

lung cancer in smokers / lung cancer in never-smokers / single-cell RNA sequencing / cellular heterogeneity

Funding

This study was supported by the National Natural Science Foundation of China (Grant No. 82388102 to H.S.) and the Research Unit of Prospective Cohort of Cardiovascular Diseases and Cancer, Chinese Academy of Medical Sciences (Grant No. 2019RU038 to H.S.).

Acknowledgments

We sincerely acknowledge all enrolled patients for their invaluable participation in this study.

The corresponding author Hongbing Shen was a former editor-in-chief of this journal but had no involvement in the editorial handling or peer review process of this manuscript. The authors reported no conflict of interests.

Additional information

The online version contains supplementary materials available at http://www.jbr-pub.org.cn/article/doi/10.7555/JBR.39.20250160?pageType=en.

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