Data from Increased Glucose Availability Sensitizes Pancreatic Cancer to Macrophage-Targeting Immunotherapies

作者：Jonathan J. Hue, Mehrdad Zarei, Priyashree Sunita, Sami O. Abul-Khoudoud, Goutam Dey, Hallie J. Graor, Katie E. Blise, Dove Keith, Shamilene Sivagnanam, Shakti Prasad Pattanayak, Erryk Katayama, Omid Hajihassani, Charles D. Lopez, Rosalie C. Sears, Robert Eil, Lisa M. Coussens, Jonathan R. Brody, Ali Vaziri‐Gohar, Jordan M. Winter · 年份：2026 · DOI：10.1158/2767-9764.c.8553229 · 研究领域：Immune cells in cancer、Pancreatic and Hepatic Oncology Research、Cancer, Hypoxia, and Metabolism

<div>AbstractPancreatic 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 fib...