SLC2A1-Dependent Ketone Metabolism Regulates Tumor Progression and Immunotherapy Efficacy in Lung Adenocarcinoma

The aim of this study is to identify and validate ketogenesis-immune cross-talk genes with prognostic significance in LUAD patients. Bulk RNA-seq data of LUAD were obtained from TCGA and GEO databases to analyze differentially expressed genes (DEGs), which were intersected with ketogenesis-related gene sets from MSigDB. DEGs associated with anti-PD-1 therapy sensitivity were further identified. Univariate and multivariate Cox regression analyses were performed to determine independent prognostic genes. Molecular subtypes and an 8-gene ketogenesis-immune prognostic signature were constructed and validated. Single-cell RNA-seq data were used to map cell-type-specific expression of prognostic genes. Functional effects of SLC2A1, a key metabolic regulator, were evaluated in A549 cells using overexpression/knockdown approaches combined with β-hydroxybutyrate (BHB) treatment. A total of 135 ketogenesis-immune cross-talk genes were identified. Consensus clustering defined two LUAD subtypes with distinct prognosis and immune landscapes. Single-cell analysis revealed SLC2A1 enrichment in epithelial tumor cells. Functional assays showed that SLC2A1 overexpression enhanced proliferation, migration, glycolysis, and ATP production, whereas knockdown suppressed these processes; BHB partially rescued energy deficits in SLC2A1-deficient cells. Mechanistically, SLC2A1 regulated ketone-body utilization and AMPK/mTOR signaling, linking metabolic reprogramming with tumor growth and immune modulation. SLC2A1 is a critical regulator of ketone-body metabolism in LUAD and serves as a potential prognostic factor.