Unveiling the altered metabolic pathways induced by nivolumab in non-small cell lung cancer via GC–MS metabolomics approach coupled with multivariate analysis

Abstract

This research investigates the effects of the immunotherapeutic agent nivolumab on the metabolism of lung cancer cells (NCI-H1975) using GC–MS metabolomic profiling. Multivariate analysis such as unsupervised PCA and supervised OPLS-DA along with univariate analysis and pathway analysis were employed to explore the metabolomic data and identify altered metabolic pathways induced by nivolumab treatment. The study revealed distinct metabolic alterations in cancer cells, linked to proliferative and survival advantages, such as enhanced glycolysis, increased glutaminolysis, and modified amino acid metabolism. Key findings indicate elevated levels of glycolysis-related metabolites (glycine, alanine, pyruvate, and lactate) and TCA cycle intermediates (succinate, fumarate, malate) in cancer cells, with a significant decrease following nivolumab treatment. Additionally, lower levels of aspartic acid and citrate in cancer cells imply altered nucleotide synthesis and fatty acid production essential for tumor growth. Treatment with nivolumab also reduced oleic acid levels, indicative of its effect on disrupted lipid metabolism. Our research shows nivolumab's potential to modify metabolic pathways involved in lung cancer progression, suggesting its dual role in cancer therapy: as an immune response modulator and a metabolic pathway disruptor.