Lactate metabolism orchestrates immune dysregulation in renal cancer: A multi-omics and causal inference study

BackgroundLactate shapes the tumor microenvironment and modulates immunity. Investigating lactate metabolism genes in renal cell carcinoma (RCC) could elucidate therapeutic targets.MethodsSingle-cell RNA sequencing (GSE242299), bulk RNA sequencing (GSE102101), and spatial transcriptomics (GSE175540) data for RCC were retrieved from GEO. Data processing included quality control, normalization, and dimensionality reduction (R packages). RCTD and CellChat were used for spatial deconvolution and cell-cell communication analysis. CIBERSORT and GSEA evaluated immune infiltration and pathway enrichment. Lactylation scores were derived via single-sample gene set enrichment analysis (ssGSEA) of lactate metabolism genes. Mendelian randomization (MR) assessed gene-cancer risk associations.ResultsMacrophages demonstrated a higher potential for interactions with other cell types due to their extensive receptor-ligand relationships. Lactylation score and MR analysis identified six pivotal genes associated with renal cancer risk: C4A and SERPINA1 were correlated with an elevated disease risk, whereas CD70, FXYD2, SERPINE1, and TUBB6 were associated with a reduced risk. These genes are linked to the degree of immune cell infiltration and can influence the disease process through diverse mechanisms. We also explored the expression profiles of primary genes involved in lactate metabolism in RCC and compared the metabolic pathways between different groups. Notably, experimental validation via tissue microarray immunofluorescence confirmed that the risk-associated genes C4A and SERPINA1 were significantly overexpressed in RCC tumor tissues.ConclusionLactic acid metabolism regulates RCC progression by modulating metabolic activity and immune cell infiltration. Key lactate metabolism genes present novel targets for RCC treatment.