Epigenetic Silencing of RFX7 Defines a Transcriptional Axis Linking Lactate Metabolism to Immune Checkpoint Therapy...

Glioblastoma (GBM) is a highly aggressive brain tumor characterized by rapid proliferation, diffuse invasion, and robust immunosuppression. Although excessive aerobic glycolysis and lactate accumulation are known to contribute to an immunosuppressive microenvironment, the upstream transcriptional mechanisms connecting metabolic reprogramming and immunotherapy resistance in GBM remain unclear. By integrating transcriptomic profiling, chromatin immunoprecipitation sequencing, and metabolic analysis with gene perturbation experiments, we identified a regulatory axis comprising RFX7 and its downstream target PIK3IP1. In GBM tissues, RFX7 expression was reduced due to promoter hypermethylation. Restoration of RFX7 enhanced PIK3IP1 expression, suppressed PI3K/AKT activation, and inhibited malignant progression in GBM. Loss of PIK3IP1 increased lactate production and histone H4K12 lactylation (H4K12la), coinciding with upregulation of PD-L1 and CSF1 and enhanced tumor immunosuppressive features. Pharmacological inhibition of lactate production with Stiripentol reduced H4K12la level, intracranial tumor growth, and immunosuppressive cell infiltration, while improving survival and response to immune checkpoint based therapy in experimental models. These findings identify an upstream transcriptional pathway linking lactate metabolism, histone lactylation, and immune suppression in GBM. Targeting the RFX7-PIK3IP1 axis provides a mechanistic rationale for metabolic-immune modulation in therapy, addressing an aspect that has remained insufficiently understood in GBM immune resistance.