Decoding the role of lipid metabolism in NSCLC : From macrophage subtype identification to prognostic model development

Abstract Lipid metabolism plays a pivotal role in shaping the tumor microenvironment, particularly by influencing macrophage function. This study aimed to identify lipid‐associated macrophage (LAM) marker genes involved in the onset and progression of non‐small cell lung cancer (NSCLC) through integrated single‐cell RNA sequencing (scRNA‐seq) and bulk RNA sequencing (bulk RNA‐seq) analyses. Mutation and RNA‐seq data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed to explore the relationship between lipid metabolism pathways and NSCLC progression. scRNA‐seq analysis revealed macrophage subtypes closely associated with lipid metabolism, with three key marker genes—S100A10, HLA‐DMB, and CTSL—identified as predictive factors for patient prognosis. A prognostic risk scoring model was constructed and validated using survival analysis and ROC curves, demonstrating high accuracy in stratifying NSCLC patients by risk. Further in vivo experiments using subcutaneous tumor xenografts and lung metastasis models showed that S100A10 and CTSL promoted tumor growth and metastasis, while HLA‐DMB inhibited these processes. Immune infiltration analysis highlighted the immunological relevance of the identified marker genes, providing insights into their functional roles. This study underscores the critical influence of LAMs in NSCLC progression and highlights a robust prognostic model that offers potential therapeutic targets for improving patient outcomes.