AUTHOR=Jiang Yan , Shu Zhengyu , Cheng Lei , Wang Haowei , He Taiping , Fu Liwen , Zhao Chao , Li Xuefei , Zeng Weicheng 

TITLE=MS4A7 based metabolic gene signature as a prognostic predictor in lung adenocarcinoma

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=Volume 12 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2025.1591446

DOI=10.3389/fmolb.2025.1591446

ISSN=2296-889X

ABSTRACT=BackgroundLung adenocarcinoma (LUAD) represents the most common form of lung cancer, contributing to significant global mortality. Metabolic reprogramming in tumor cells has been increasingly recognized as a hallmark of tumorigenesis, contributing to an immunosuppressive microenvironment. Given the promising prediction value of metabolism-related genes in LUAD, this study aims to explore the role of MS4A7, a member of the MS4A gene family, in LUAD prognosis and immune microenvironment dynamics.MethodsA prognostic signature for LUAD was developed using the LASSO-Cox regression algorithm with RNA-seq data from 500 LUAD patients in The Cancer Genome Atlas database. Genes with differential expression linked to metabolic pathways were identified, and 20 genes were included to develop a risk signature. Further functional enrichment analysis was conducted to compare the biological pathways activated in high-risk versus low-risk groups. Single-cell RNA sequencing was employed to identify the expression profile and role of MS4A7 in different macrophage populations within the LUAD.ResultsThe constructed prognostic model displayed high predictive accuracy, outperforming single gene-based predictions. High-risk patients exhibited significantly poorer survival outcomes. Pathway enrichment analysis revealed dysregulated metabolic pathways in high-risk patients, including activation of glycolysis, mTORC1 signaling, and ROS production. Single-cell RNA sequencing revealed that MS4A7 expression was predominantly found in macrophage populations, with high expression localized in MS4A7+ macrophages. These macrophages exhibited distinct metabolic reprogramming and key immune functions, particularly in crosstalk with T cells and neutrophils.ConclusionThe MS4A7 gene plays a critical role in LUAD prognosis, particularly through its involvement in immune modulation within the TME. MS4A7+ macrophages, characterized by distinct metabolic reprogramming and immune interactions, are pivotal in shaping LUAD progression and immune response. The findings highlight the potential of MS4A7 as a novel prognostic biomarker and therapeutic target for LUAD. Further investigation into the metabolic and immune regulatory mechanisms of MS4A7+ macrophages could offer new insights into LUAD treatment strategies.