Integrative multi-omics reveal NSUN2 facilitates glycolysis and histone lactylation-driven immune evasion in renal carcinoma.

Clear cell renal carcinoma (ccRCC) is the most prevalent and aggressive subtype of kidney cancer. Targeting ccRCC metabolism is a promising therapeutic strategy, and some metabolic targets are currently undergoing clinical trials. Here, we collected multiple ccRCC clinical cohorts, including bulk RNA sequencing and single-cell sequencing datasets, to investigate mitochondrial metabolic genes' prognostic and therapeutic potential. Integrating 10 machine learning algorithms, we constructed 117 predictive models, with the optimal model selected and defined as Mitoscore for patient stratification and treatment. Furthermore, NSUN2, an RNA 5-methylcytosine (m5C) methyltransferase, was identified as the most important gene in the model and selected for further gene function experiments in vitro and in vivo. NSUN2 promoted cell proliferation, migration, and invasion; reprogrammed glycolysis metabolism and histone lactylation levels via maintaining NEO1 mRNA stability. In addition, NSUN2 increased PD-L1 expression in tumor cells via the MYC/POM121/CD274 axis in a lactylation-dependent manner. Knockdown of NSUN2 enhanced CD8 T cell killing effects in vitro, along with TNF-α + T cell infiltration in vivo. These results highlight that mitochondrial genes are optional therapeutic targets and prognostic markers; NSUN2 promotes mitochondrial glycolysis and histone lactylation in an m5C-dependent manner, thereby resulting in PD-L1-mediated immune escape, which elucidates novel NSUN2-mediated crosstalk between glycolysis and immune evasion.