Increased Glucose Availability Sensitizes Pancreatic Cancer to Macrophage-Targeting Immunotherapies.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive tumor microenvironment (TME) that limits the efficacy of immunotherapies. Many tumor-suppressive immune cells, including inflammatory macrophage subsets, rely on glycolysis to sustain effector function; however, the pancreatic TME is relatively glucose-limited. In this study, we investigated whether increasing glucose availability in the periphery, which in turn translates to increased intratumoral glucose, could enhance immune-based therapies in PDAC. In vitro, glucose restriction induced metabolic reprogramming of inflammatory (M1-like) macrophages toward an oxidative, M2-like state with reduced inflammatory effector markers. In immunocompetent mice, administration of 30% dextrose drinking water increased both peripheral and intratumoral glucose levels and modestly shifted tumor transcriptional profiles toward a more inflammatory state without altering overall immune cell abundance. When macrophage-targeting immunotherapies (colony stimulating factor 1 receptor inhibition with PLX3397 or C-C chemokine receptor type 2 inhibition with PF-4136309) were combined with systemic hyperglycemia, tumors exhibited a pronounced increase in iNOS+ M1-like macrophages, a reduction in arginase+ M2-like macrophages, enhanced CD8+ T-cell infiltration, and decreased abundance of tumor-associated fibroblasts. These immunotherapies improved overall survival in immunocompetent mice bearing orthotopic pancreatic tumors only when combined with hyperglycemia. Analyses of patient samples confirmed the presence of a favorable antitumor immune infiltrate with elevated glucose levels. Together, these findings identify glucose availability as a key regulator of macrophage polarization and immunotherapy efficacy in PDAC. SIGNIFICANCE: PDAC is largely resistant to immunotherapies. Our findings identify glucose availability in the TME as a modifiable determinant of macrophage polarization and immunotherapy response. In preclinical models, transient hyperglycemia was associated with enhanced efficacy of macrophage-targeting immunotherapies and promoted a more inflammatory TME.