Integrating metabolism and immunity: targeting lactate-mediated mechanisms in PDAC

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and responds poorly to immune checkpoint inhibitors. Lactate is abundant in the tumor microenvironment and is associated with immune evasion. This study examined the regulatory role of lactate and evaluated metabolism-immunity targeting strategies in PDAC. We used PDAC cell models exposed to lactate and xenograft mice, applying N1-methyladenosine RNA immunoprecipitation, ribosome profiling, and transcriptome analyses to examine lactate’s effects via the TRMT6-SIRT5 axis. The efficacy of CDK4/6 inhibitors combined with lactate metabolism blockers was also tested. Lactate significantly enhanced N1-methyladenosine RNA modification by TRMT6, increasing translation of key metabolic enzymes and driving reprogramming. It activated SIRT5-mediated desuccinylation, boosting TCA cycle enzyme activity and oxidative metabolism. Lactate upregulated PD-L1 via the TRMT6-SIRT5 axis, enhancing CDK4/6 signaling and immune evasion. Combining lactate blockers with CDK4/6 inhibitors reduced PD-L1 expression, restored T cell function, and improved anti-PD-1 therapy efficacy in mice. Lactate may promote metabolic reprogramming and immune evasion in PDAC through the TRMT6-SIRT5 axis, linking metabolism, epigenetic regulation, and antitumor immunity. Combining CDK4/6 inhibition with lactate blockade may provide a rationale for improving immunotherapy responses in pancreatic cancer.