Tumor-infiltrating natural killer cell profiling for therapeutic stratification in patients with resectable non-small cell lung cancer.

[OBJECTIVE] Neoadjuvant chemoimmunotherapy has improved outcomes in resectable non-small cell lung cancer (NSCLC), yet its real-world implementation is often challenged by surgical delays, immune-mediated fibrosis, and postoperative complications. Smokers with NSCLC, 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 (scRNAseq) was performed on 61 lung tissues from non-smokers and smokers to identify smoking-related immune compositions. The scRNAseq data from 19 invasive lung adenocarcinomas were used to validate their presence in the tumor-immune microenvironment. Bulk RNA sequencing data from 102 resected NSCLC and 24 NSCLC patients treated with neoadjuvant chemoimmunotherapy followed by surgery were used for in silico cellular deconvolution and outcome analyses.

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

[CONCLUSIONS] Intratumoral NK cell phenotyping may aid in therapeutic stratification in patients with NSCLC. NK cell preservation predicts benefit from upfront surgery, while NK cell enrichment indicates improved response to neoadjuvant chemoimmunotherapy. These NK cell profiles may help optimize treatment by balancing therapeutic benefit and risk.