Abstract 6137: Inhibition of FXR signaling in tumor-associated myeloid cells protects against melanoma progression

Abstract Our study delves into the complex interplay between the tumor microenvironment and immune cell regulation, with a particular focus on myeloid-derived suppressor cells (MDSCs). A key discovery of our research is the accumulation of bile acids (BAs) within the tumor microenvironment and tumor-infiltrating myeloid cells. BAs significantly enhance the suppressive function of MDSCs and M2 macrophages via activation of Farnesoid X Receptor (FXR).Using melanoma as our primary model. We demonstrate that modulation of MDSCs' suppressive function can be achieved through the targeting FXR using specific agents like GW4064 and z-Guggulsterone (z-GS). Myeloid-specific elimination of FXR via Lysozyme M Cre led to a significant delay in tumor progression. This was accompanied by the reduction of PMN-MDSC and an increased infiltration of CD45 positive immune cells and a surge in the presence of anti-tumor specific T cells. Administration of FXR inhibitor, z-GS, through oral gavage also reduced tumor size in vivo. Additionally, targeting FXR by z-GS or myeloid specific genetic ablation enhances adoptive T cells transfer therapy efficacy. MDSCs with impaired FXR signaling result in reduced mitochondria activity and downregulation of Arg1. Furthermore, an enhanced antigen presentation function is observed in MDSCs and dendritic cells treated with z-GS. Our research presents a compelling case for targeting FXR signaling in myeloid cells as a novel therapeutic strategy and open new pathways for enhancing anti-tumoral immunity. Citation Format: Shiun Chang, Darwin C. Chang, Rachel V. Jimenez, Rosa A. Sierra-Mondragon, Julio A. Vazquez Martinez, Paulo C. Rodriguez. Inhibition of FXR signaling in tumor-associated myeloid cells protects against melanoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6137.