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Tumor and stromal cell plasticity induced by different tumor microenvironments (TMEs) has a significant impact on tumorigenesis of colorectal carcinoma (CRC). Specifically the role of the immunological TME has been investigated intensively. The prognosis of CRC is influenced by the density and localization of infiltrating T cells. Moreover, the presence of an mRNA expression profile indicative of a type 1 adaptive immune response (high IFN-γ and IFN-induced gene expression, cytotoxic T cell (CTL) signature) represents a positive prognostic factor for patients with CRC. IFN-γ is a major mediator of the Th1 immune response, which is produced by NK, NKT, Th1 cells and CTL. The role of IFN-γ in anti-tumor immune response has been mainly attributed to the immune-modulatory activity of the cytokine, such as the recruitment and activation of cytotoxic T-cells or monocytes. However, the expression of the IFN-γ receptor is ubiquitous and studies of IFN-γ-induced genes expression in CRC revealed that many different cell types are stimulated by the cytokine within a tumor, including tumor cells and stromal cells such as macrophages/monocytes and endothelial cells. In vitro, IFN-γ shows anti-tumorigenic activities in CRC cell lines, activates monocytes and exerts potent anti-angiogenic effects on endothelial cells. Here we investigated the cell-type-specific impact of the response to IFN-γ on CRC development using mouse strains with conditional knock-out of the IFN-γ receptor in intestinal epithelial cells (Villin-Cre), T-cells (CD4-Cre), myeloid cells (CD11b-Cre) and endothelial cells (Tie2-Cre + BMT). Tumor growth was chemically induced by injection of azoxymethane combined with three cycles of treatment with dextran-sodium sulfate. This model recapitulates inflammation-induced carcinogenesis. Our results revealed increased tumor numbers and load when the IFN-γ response was blocked in epithelial cells, despite an initial attenuation of inflammation. Tumors that developed in Ifngr2-Villin-Cre mice showed an attenuated IFN-γ response, and a decrease of CD8+ T cell infiltration, cell death and hypoxia. Abrogation of the IFN-γ-response in endothelial cells also fostered tumor growth, which could be attributed to an increase of angiogenesis. Surprisingly, only a modest effect was seen in the T-cell-specific knock-out, in comparison to the myeloid-specific knock-out, which was associated with a strong increase of tumor numbers and load. The latter indicated that the anti-tumorigenic activity mediated by IFN-γ relies to a larger extent on the innate than on the adaptive immune response. Our study documents that the anti-tumorigenic activity of IFN-γ is based on direct effects on epithelial tumor cells and on the vasculature, as well as on the involvement of the innate immune response. Citation Format: Nathalie Britzen-Laurent, Wei Guo, Victoria Langer, Svetlana Khoziainova, Thomas Weisenburger, Thomas H. Winkler, Julia Straube, Maximilian J. Waldner, Christoph Becker, Elisabeth Naschberger, Lisa Skottke, Tripal Philipp, Sergei Grivennikov, Michael Stürzl. Role of IFN-gamma-activation of distinct tumor and stromal cell populations in colorectal carcinoma pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5162.