uPAR expression in M-MDSCs under high LDHA activity in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive tumor microenvironment (TME), which limits treatment efficacy. Lactate, produced from pyruvate by lactate dehydrogenase A (LDHA), is known to contribute to the formation of such an immunosuppressive TME. However, it remains unclear how lactate metabolism influences immune cell populations and contributes to immunosuppression under metabolic constraints in PDAC. To address this, we investigated the mechanisms by which a high-LDHA TME promotes an immunosuppressive landscape in PDAC using single-cell RNA sequencing and multiplex immunofluorescence staining. In a mouse Ldha-knockdown (shLdha) PDAC model characterized by reduced glucose consumption and lactate production, the number of myeloid-derived suppressor cells (MDSCs) was markedly reduced compared to controls. Gene set enrichment analysis revealed lower enrichment of the cholesterol metabolism pathway in MDSCs from the shLdha group. Among cholesterol-associated genes, PLAUR, which encodes the urokinase plasminogen activator receptor (uPAR), showed the highest expression in MDSCs, particularly in monocytic MDSCs (M-MDSCs). In human PDAC samples, patients with high LDHA expression exhibited greater numbers of M-MDSCs and a higher proportion of uPAR-positive M-MDSCs compared to those with low LDHA expression. These findings provide mechanistic insights into how lactate metabolism in the high-LDHA TME modulates MDSC behavior and contributes to immunosuppression in PDAC.