Language

English

Publication Date

8-1-2026

Journal

The Journal of Thoracic and Cardiovascular Surgery

DOI

10.1016/j.jtcvs.2026.02.030

PMID

41791482

PMCID

PMC13513242

PubMedCentral® Posted Date

8-27-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Objective: Neoadjuvant chemoimmunotherapy has improved outcomes in resectable non-small cell lung cancer, yet its real-world implementation is often challenged by surgical delays, immune-mediated fibrosis, and postoperative complications. Smokers with non-small cell lung cancer, despite a high risk for surgical morbidity, show enhanced responses to neoadjuvant chemoimmunotherapy. This study aimed to identify smoking-associated immune cell determinants that could guide treatment strategies.

Methods: Single-cell RNA sequencing was performed on 61 lung tissues from nonsmokers and smokers to identify smoking-related immune compositions. The single-cell RNA sequencing data from 19 invasive lung adenocarcinomas were used to validate their presence in the tumor-immune microenvironment. Bulk RNA sequencing data from 102 patients with resected non-small cell lung cancer and 24 patients with non-small cell lung cancer treated with neoadjuvant chemoimmunotherapy followed by surgery were used for in silico cellular deconvolution and outcome analyses.

Results: Among 135 lung cellular phenotypes, 2 natural killer cell subsets were strongly associated with smoking and chronic obstructive pulmonary disease severity. "Stress-responsive" natural killer cells exhibited immature features and cytokine-responsive features, and "adaptive and immunoregulatory natural killer" cells showed mature features and elevated multiple immune checkpoint expression. High intratumoral "stress-responsive" natural killer cells correlated with improved survival after surgery, particularly in current smokers. Conversely, tumors with low "stress-responsive" natural killer and high "adaptive and immunoregulatory natural killer" cells responded more favorably to neoadjuvant chemoimmunotherapy.

Conclusions: Intratumoral natural killer cell phenotyping may aid in therapeutic stratification in patients with non-small cell lung cancer. "Stress-responsive" natural killer cell preservation predicts benefit from up-front surgery, whereas "adaptive and immunoregulatory natural killer" cell enrichment indicates improved response to neoadjuvant chemoimmunotherapy. These natural killer cell profiles may help optimize treatment by balancing therapeutic benefit and risk.

Keywords

Humans, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Killer Cells, Natural, Male, Neoadjuvant Therapy, Female, Lymphocytes, Tumor-Infiltrating, Middle Aged, Aged, Smoking, Tumor Microenvironment, Pneumonectomy, Risk Factors, Treatment Outcome, cellular biomarker, chronic obstructive pulmonary disease, natural killer cell, neoadjuvant chemoimmunotherapy, non–small cell lung cancer, predictive marker, prognostic marker, single-cell RNA sequencing, smoking

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.