LDHA facilitates immune escape in bladder cancer through H4K5 lactylation-dependent upregulation of PD-L1

Abstract

Metabolic reprogramming, characterized by hyperactive glycolysis, is a hallmark of bladder cancer (BCa) progression. Here, we identify lactate dehydrogenase A (LDHA) as a central metabolic node coupling glycolytic flux to epigenetic regulation of the immune checkpoint molecule PD-L1. Transcriptomic and survival analyses reveal that dysregulated glycolytic enzymes, particularly LDHA, correlate with poor prognosis and immunotherapy response in BCa patients. Mechanistically, LDHA-driven lactate production induces histone H4K5 lactylation (H4K5la), facilitated by the acetyltransferase EP300, which directly activates PD-L1 transcription. Depletion of LDHA or EP300 reduces H4K5la levels and suppresses PD-L1 expression. Critically, EP300 knockdown reverses PD-L1 upregulation induced by LDHA overexpression, establishing a causal LDHA-EP300-H4K5la-PD-L1 axis that drives immune evasion. Furthermore, RNA immunoprecipitation and luciferase reporter assays suggest that m6A RNA modification may potentiate LDHA overexpression. Collectively, this work unveils a dual-layered mechanism-metabolic lactate flux and histone lactylation that orchestrates immune evasion in BCa, proposing LDHA and EP300 as actionable targets to restore antitumor immunity.

Keywords: Bladder cancer; Histone lactylation; Immune escape; Immunotherapy; LDHA; PD-L1.