Integrated multi-omics reveals glycolytic gene signatures of lung adenocarcinoma brain metastasis and the impact of Rac2 lactylation on immunosuppressive microenvironment

作者：Yali Yi, Wenjie Xu, Hao Yu, Yuxi Luo, Fujuan Zeng, Daya Luo, Zhimin Zeng, Le Xiong, Long Huang, Jing Cai, Anwen Liu · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-07207-6 · 被引用次数：9 · 研究领域：Cancer, Hypoxia, and Metabolism、Immune cells in cancer、Cancer Cells and Metastasis

PURPOSE: Tumor Metabolic Behavior modulates the immunosuppressive microenvironment through multiple pathways, thereby compromising anti-tumor immune responses. To date, there have been limited studies assessing the role of metabolic plasticity or immunometabolism in the tumor microenvironment (TME) during metastasis. Notably, emerging evidence suggests the presence of an immunosuppressive niche in brain metastases. This research aims to delineate distinct metabolic signatures in brain metastatic, investigate the impact of tumor-associated glycolysis on the development of brain metastases in lung adenocarcinoma, and characterize the lactylation regulation in this immunosuppressive microenvironment. METHODS: The GSE131907 and GSE198291 datasets were retrieved for bioinformatic analysis. Combined with the results of proteomic and transcriptomic sequencing conducted on the lung adenocarcinoma brain metastasis model, differentially expressed signaling pathways were systematically identified through KEGG and GO functional annotations. A multimodal approach encompassing immunohistochemical (IHC) staining, immunofluorescence (IF) imaging, enzyme-linked immunosorbent assay (ELISA) quantification, and co-immunoprecipitation (Co-IP) assays was employed to experimentally validate the characteristics of the immunosuppressive microenvironment and the levels of tumor lactate/lactylation. Rescue experiments were performed by adding a lactylation-specific inhibitor (LDHi) or an H3K18la site-s...