Monocarboxylate Transporter 2 (MCT2) Mitigates Lung Tumor Progression by Shaping the Immune Microenvironment [bulk RNA]

Monocarboxylate transporter 2 (MCT2; SLC16A7) is a high-affinity pyruvate transporter implicated in cancer metabolism. However, its role in lung cancer progression and the tumor microenvironment remains unclear. This study examined the effects of MCT2 loss on tumor growth and cell type-specific transcriptional changes within the tumor microenvironment. MCT2 loxP/loxP mice were crossed with mCre-Tg mice, and MCT2 deletion was induced by tamoxifen. Control (CO) mice received vehicle treatment. TC1 cells (100,000 cells/mouse) were injected subcutaneously, and tumors were harvested after 24 days. Single-nucleus RNA sequencing (snRNA-seq) was performed on isolated tumor nuclei (4,000 nuclei/sample; n = 3 per group) using the 10x Genomics Chromium platform. Data were processed with Cell Ranger v3.0.2 and Seurat v5.2.1, followed by differential expression and pathway enrichment analyses integrated with macrophage bulk RNA-seq data. MCT2-deficient tumors grew significantly faster than control tumors, supporting a tumor-suppressive role for MCT2. Transcriptomic analysis generated high-quality profiles from 7,840 CO and 10,175 KO nuclei. Clustering identified 10 cellular populations, including nine annotated cell types. MCT2 deficiency altered pathways involved in glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, and fatty acid metabolism across multiple populations. Macrophages showed prominent transcriptional changes, including enrichment of MAPK, PI3K-Akt, IgSF-CAM, and cell adhesion molecule signaling pathways. These findings were supported by macrophage bulk RNA-seq data. MCT2 deficiency enhances tumor growth and induces widespread transcriptional remodeling of the tumor microenvironment. Altered metabolic and immune-related pathways, particularly in macrophages, may contribute to lung cancer progression and represent potential therapeutic targets.