Abstract LB053: Targeting macrophage metabolism in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDA) remains one of the leading causes of cancer-related mortality in the United States, despite its relatively low incidence rate. A significant challenge in treating PDA lies in its densely fibrotic tumor microenvironment, which is heavily infiltrated by immune cells. This environment is characterized by limited functional vasculature, restricting nutrient availability, and facilitating complex interactions between tumor cells and immune populations, such as tumor-associated macrophages (TAMs). These conditions drive cancer cells to adopt diverse metabolic adaptations. One notable example is the metabolic enzyme Arginase 1 (ARG1), which catalyzes the breakdown of the amino acid L-arginine into urea and ornithine. Previous studies have shown a connection between arginine metabolism and macrophage effector function along the M1/M2 axis. In macrophages, arginine can be broken down in two ways: via inducible nitric oxide synthase (iNOS) into nitric oxide, which aids in effector function, or via Arginase 1 (ARG1) into ornithine and later proline, which is an essential component of the extracellular matrix (ECM). Additionally, it has been demonstrated that ARG1 is highly expressed in tumor-associated macrophages (TAMs), where it fosters an immune-suppressive phenotype, positioning it as a compelling therapeutic target. Thus, building on this foundation we have developed mouse models with a macrophage-specific knockout of Arg1. Utilizing this model, we are investigating the phenotypic effects of disrupting this metabolic pathway within macrophages in the contexts of both PDA and its major predisposing factor, pancreatitis. Citation Format: Austin D. Silva, Sabrina E. Calderon, Rima Singh, Cecily Anaraki, Taryn Morningstar, Anai C. Contreras, Natalie Yousefian, Avary S. Baker, Christopher Halbrook. Targeting macrophage metabolism in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB053.