Lactate-modulated immunosuppression of myeloid-derived suppressor cells contributes to the radioresistance of pancreatic cancer.

The mechanisms responsible for radioresistance in pancreatic cancer have yet to be elucidated and the suppressive tumor immune microenvironment must be considered. We investigated if the radiotherapy-augmented Warburg effect helped myeloid cells acquire an immunosuppressive phenotype, resulting in limited treatment efficacy of pancreatic ductal adenocarcinoma (PDAC). Radiotherapy enhanced the tumor-promoting activity of myeloid-derived suppressor cells (MDSCs) in pancreatic cancer. Sustained increase in lactate secretion, resulting from the radiation-augmented Warburg effect, was responsible for the enhanced immunosuppressive phenotype of MDSCs after radiotherapy. Hypoxia-inducible factor-1α (HIF-1α) was essential for tumor cell metabolism and lactate-regulated activation of MDSCs via the G protein-coupled receptor 81 (GPR81)/ mammalian target of rapamycin (mTOR)/HIF-1α/STAT3 pathway. Blocking lactate production in tumor cells or deleting Hif-1α in MDSCs reverted antitumor T cell responses and effectively inhibited tumor progression after radiotherapy in pancreatic cancer. Our investigation highlighted the importance of radiation-induced lactate in regulating the inhibitory immune microenvironment of PDAC. Targeting lactate derived from tumor cells and the HIF-1α signaling in MDSCs may hold distinct promise for clinical therapies to alleviate radioresistance in PDAC.