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Multi-omics integration reveals that pyrimidine metabolism in lung adenocarcinoma drives an immunosuppressive
Miaoyan Liu1, Houqiang Li1, Shenghan Xu1
1Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, China.
Abstract:
Metabolic reprogramming in lung adenocarcinoma (LUAD) profoundly shapes the tumor immune microenvironment (TIME), yet the immune-regulatory role of pyrimidine metabolism remains unclear. This study investigates the mechanisms and clinical significance of pyrimidine metabolism in LUAD. Multi-omics analysis identified pyrimidine metabolism as a key prognostic pathway. A machine learning-based risk model revealed nine core genes, with MCM7 as a central driver. Single-cell and spatial transcriptomic analyses showed that high-pyrimidine-metabolism tumor cells interact with immune cells via enhanced migration inhibitory factor (MIF) signaling. Functional assays confirmed that MCM7 knockdown suppresses LUAD proliferation and migration. Mechanistically, MCM7 regulates pyrimidine synthesis enzymes (DHODH and UMPS), activates the ERK pathway, and interacts with the MIF-CD74 axis. These findings indicate that MCM7 serves as a critical link connecting pyrimidine metabolic reprogramming to the regulation of the TIME in LUAD.
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