Impaired natural killer cell maturation in lung adenocarcinoma driven by and downregulation through disrupted lipid metabolism.

BACKGROUND

Although natural killer (NK) cells play a crucial role in antitumor immunity, the metabolic changes driving their dysfunction in lung adenocarcinoma remain poorly understood. This study investigates how these metabolic modifications impact NK cell function within the lung adenocarcinoma microenvironment.

METHODS

A total of 13 pairs of lung adenocarcinoma samples were obtained from The Cancer Genome Atlas. Differential gene expression, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and single-cell metabolic quantification analyses were used to characterize the transcriptomic, pathway, and metabolic signatures of NK cells. The developmental trajectory was reconstructed via pseudotime analysis. The fatty acid-binding protein 4 () and spondin2 () expression was examined using immunofluorescence (IF) and immunohistochemistry (IHC) in patients with lung adenocarcinoma. In NK cells with downregulation, function was analyzed using antibody-independent cell-mediated cytotoxicity assays, flow cytometry (FCM), and liquid chromatography-mass spectrometry.

RESULTS

The number of NK cells was significantly decreased in the lung adenocarcinoma microenvironment. and expression was significantly lower in NK cells within tumor tissues than in the adjacent tissues. FABP4 expression was significantly lower in tumor tissues than in the adjacent tissues, whereas no significant difference in SPON2 expression was observed. The cytotoxic function of NK cells with decreased levels was impaired. Non-targeted lipid metabolism analysis indicated that differentially expressed lipids in NK cells with low levels were functionally enriched in the glycerophospholipid metabolism pathway compared to those in normal NK cells.

CONCLUSIONS

The study findings present new evidence showing that low and gene expression may impair NK cell maturity by affecting lipid metabolism in lung adenocarcinoma. These results provide a new perspective on restoring immune function in patients with lung cancer.