Endothelial AGO1 Deficiency Reduces Breast Cancer Burden in Mice

Endothelial cells are crucial in cancer development and progression, in part through tumor angiogenesis and immune modulation. As a key component of RNA-induced silencing complex, Argonaute 1 (AGO1) protein has been shown to regulate tumor biology. However, its role in ECs within the tumor microenvironment remains undefined. In this study, we investigated the effects of EC-conditional AGO1 knockout (EC-AGO1-KO) on tumor vascularization and immune regulation in a mouse xenograft breast cancer model. EC-AGO1-KO developed significantly reduced tumor burden when compared to their wild-type littermates. The tumor suppression was accompanied by lower tumor vascularization and stronger immune infiltration. Histological and single cell RNA sequencing analysis revealed that tumors in the EC-AGO1-KO mice exhibited increased CD8⁺ T cells and macrophages, reflecting a pro-immunostimulatory microenvironment. In vitro experiments show that EC-AGO1-knockdown (AGO1-KD) conditioned media suppresses breast cancer cell migration, attendant with the downregulation of C-X-C chemokine receptor type 4 (CXCR4) and upregulation of RUNX1 Partner Transcriptional Co-Repressor 1 (RUNX1T1). These findings suggest that EC-AGO1 plays a crucial role in regulating tumor angiogenesis and immune cell infiltration, thereby influencing tumor progression. Targeting EC AGO1 may offer a novel therapeutic strategy for disrupting tumor vascularization while enhancing anti-tumor immunity.