Abstract A055: Targeting myeloid metabolism to remodel the pancreatic tumor immune microenvironment

Abstract Pancreatic ductal adenocarcinoma (PDA) is projected to become the 2nd most prevalent cancer-related death in the United States. The lethality of PDA is largely due to a lack of effective treatment options. A principal barrier in PDA treatment is the physiology of the tumors, characterized by a densely fibrotic stroma rich with immune cell infiltration. Most of these immune cells are immunosuppressive myeloid cells, including macrophages, polarized by environmental cues that dictate their function. This polarization has typically been thought of as pro-inflammatory or anti-inflammatory. In PDA, macrophages within the tumor, termed tumor-associated macrophages (TAMs), are strongly immunosuppressive, inhibiting both infiltration and activation of cytotoxic T cells. Further, TAMs have been shown to directly inhibit chemotherapy in PDA. Accordingly, targeting or reprogramming TAMs may sensitize pancreatic cancer to multiple treatment strategies. We and others have shown that the polarization of macrophages to a pro and anti-inflammatory state drives the adaptation of specific metabolic programming. Specifically, anti-inflammatory macrophages, including TAMs, preferentially use mitochondrial metabolism for bioenergetics. Accordingly, this provides a potential avenue to employ metabolic intervention to reprogram or eliminate pro-cancer TAM populations. To examine if targeting mitochondrial metabolism can impair the functional anti-inflammatory properties of macrophages we have generated a model to genetically ablate a transcription factor required for ETC assembly in a myeloid-specific manner. Our preliminary data demonstrate that mice harbor harboring defective oxidative metabolism in myeloid cells have an altered response to pancreatic inflammation. Moving forward with these models we expect to use these models to investigate the role of myeloid mitochondrial metabolism on pancreatic tumorigenesis, immune suppression in the pancreatic tumor microenvironment, and PDA response to therapy. Citation Format: Mariam Mohagheghi, Austin Silva, Avary Baker, Ethan Smiggs, Dequina Nicholas, Christopher Halbrook. Targeting myeloid metabolism to remodel the pancreatic tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A055.