Beyond the tumor: Enhancing pancreatic cancer therapy through glutamine metabolism and innovative drug delivery.

Pancreatic ductal adenocarcinoma (PDAC) depends a lot on how it uses glutamine to grow quickly and stay alive. Oncogenic drivers such as KRAS, c-Myc, and HIF-1α increase how much glutamine gets taken up and broken down. Meanwhile, the bacteria in the gut and tumor itself also affect how much glutamine is available throughout the body and near the tumor. This impacts both how the tumor grows and how the immune system can detect and respond to it. Multiple strategies have emerged to disrupt this dependence: glutamine antagonists (DON and its prodrugs DRP-104, JHU-083), small-molecule glutaminase inhibitors (CB-839), antibody-drug conjugates targeting the ASCT2 transporter, and combination regimens pairing glutamine blockade with immune checkpoint inhibitors. Nanoparticle formulations-including pH-sensitive and PEGylated liposomes co-delivering DON and gemcitabine-enable targeted delivery and reduce off-target toxicity. Single-agent treatments do not work so well because the cells can adapt. They boost enzymes such as asparagine synthetase and increase how they burn fatty acids to make up for the lack of glutamine. To overcome these escape routes, future interventions must concurrently target compensatory pathways and integrate biomarker-driven patient selection. Combining glutamine-targeted agents with inhibitors of asparagine synthesis or lipid oxidation, guided by multi-omics profiling, promises a more durable therapeutic benefit and lays the groundwork for personalized treatment of PDAC.