FTO mediated glycolytic metabolism for papillary renal cell carcinoma immune evasion

N6-methyladenosine (m6A) methylation is the predominant internal modification in eukaryotic mRNA, characterized by the methylation of adenosine at the nitrogen-6 position. A key m6A demethylase, the Fat Mass and Obesity-associated protein (FTO) play a significant role in metabolism. Renal cell carcinoma (RCC), particularly papillary RCC, is characterized by increased glucose uptake and a shift towards anaerobic glycolysis, commonly known as the “Warburg effect”. This study investigates the role of FTO in glycolytic reprogramming and immune evasion in RCC. FTO disruption resulted in a Lactate Dehydrogenase A (LDHA) expression downregulation, followed by lactate production reduction and CD8 + T cells activation. Furthermore, FTO pharmacological inhibition by DAC51 promoted CD8 + T cell activation, also resulting in increased apoptotic activity. These findings reveal a novel role for FTO in regulating tumor metabolism and immune escape in pRCC, highlighting its potential as a therapeutic target for cancer immunotherapy.