Abstract Background; Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, and liver metastasis is the leading cause of mortality. Within the tumor microenvironment (TME), macrophages play central roles regulating inflammation and antitumor immunity. However, the specific contribution of macrophage-intrinsic IFN-γ signaling to metastatic progression remains poorly understood. Methods; To investigate the role of IFN-γ signaling in macrophages, we established a portal vein injection model of PDAC liver metastasis using Ifngr2flox/flox LysM-Cre mice. Tumor burden was quantified by gross morphology and histology. Flow cytometry was used to assess macrophage and other immune cell abundance and phenotypes/activation states. Bulk RNA sequencing (Bulk RNA-seq) on whole liver metastases and single-cell RNA sequencing (scRNA-seq) on immune cell types were performed to examine the effect of myeloid-specific IFN-γ signaling on metastatic TME. Results; We found that IFNgr2 myeloid specific deletion led to a marked increase in metastasis number and overall tumor load compared with WT controls. Flow cytometric analysis demonstrated that tumor associated macrophages (TAMs) in IFNgr2ΔMye mice showed increased Arg1 and CD206 expression and reduced MHC-II, CD80, and CD86, indicating a shift toward an immunosuppressive phenotype. Bulk RNA-seq revealed down-regulation of IFN-γ response, antigen presentation, and inflammatory pathways in metastases from IFNgr2ΔMye mice. ScRNA-seq analysis further uncovered profound remodeling of macrophage compartment with elevation in TREM2 high lipid-associated macrophages and angiogenic TAMs, accompanied by enhanced TGF-β signaling and fibrotic matrix gene expression. Conclusions; Loss of macrophage-intrinsic IFN-γ receptor signaling drives the expansion of TREM2 high and angiogenic TAM subsets, promoting an immunosuppressive and fibrosis-prone TME that facilitates PDAC liver metastasis. These findings highlight the IFN-γ-macrophage axis as a critical regulator of metastatic progression and a potential therapeutic target in PDAC. Citation Format: Takeshi Tanaka, Elena Ivleva, Ali Savas, Katarzyna Chojnacka, Sergei Grivennikov, . Myeloid IFN-γsignaling regulates immunosuppressive and fibrotic tumor microenvironment in PDAC liver metastasis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6790.
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