UBE2T‐Driven p53 Degradation Rewires Glycolysis to Orchestrate Lactylation‐Mediated CAFs Activation and ECM Deposition in Pancreatic Cancer

ABSTRACT Although glycolysis is a metabolic hallmark of pancreatic ductal adenocarcinoma (PDAC), it remains unclear whether the excessive lactate produced regulates CAF lactylation to promote extracellular matrix (ECM) deposition. The multi‐omics and spontaneous model findings indicate that lactate accumulation in the tumor microenvironment (TME) promotes histone H3 lysine 18 lactylation (H3K18la) and activation of cancer‐associated fibroblasts (CAFs), leading to both ECM densification and impaired immunotherapy efficacy in PDAC. Mechanistically, ubiquitin‐conjugating enzyme E2T (UBE2T) acts as an initiating factor that promotes p53 positive feedback degradation through modulation of ribosome biogenesis, thereby enhancing lactate metabolic crosstalk via glycolytic reprogramming. Genetic ablation or pharmacological inhibition of UBE2T using the selective inhibitor pentagalloylglucose (PGG) disrupts lactate metabolic crosstalk, suppresses stromal deposition, and promotes intratumoral CD8 + T cells infiltration. Furthermore, the combination of PGG and anti‐PD‐1 therapy exhibits synergistic effects and survival benefits in spontaneous PDAC mice and immune‐reconstituted patient‐derived xenografts. Collectively, these findings reveal that UBE2T drives p53 positive feedback degradation to enhance glycolysis of PDAC, leading to excessive lactate production, which promotes H3K18la in CAFs and subsequent ECM deposition. Targeting UBE2T represents a potential strategy to improve the efficacy of immunotherapy in PDAC.