Triple-negative breast cancer (TNBC) is characterized by systemic spread and a lack of targeted therapies. Metastasis is a systemic process facilitated by the formation of the pre-metastatic niche (PMN), a distant organ environment primed by tumor-derived factors. Our preliminary data identify sirtuin 1 (SIRT1) as a suppressor of this pro-metastatic secretome. We have discovered that SIRT1 loss promotes IGF2BP2-mediated degradation of the ATP6V1A transcript, which encodes a critical catalytic subunit of the vacuolar-type ATPase (v-ATPase) complex that is responsible for maintaining the pH of lysosomes. This loss of lysosomal acidification alters exosomal secretion, which can reprogram distant tissues into receptive environments for colonization. I hypothesize that SIRT1-deficient TNBC cells accelerate metastasis by producing a metabolic secretome that establishes a pro-inflammatory and senescent-rich pulmonary PMN. Using murine models and untargeted metabolomics, I will characterize the metabolic cargo of SIRT1- deficient exosomes and use 13C-labeled tracing to determine how these vesicles reprogram distant stromal cells. In vivo imaging will define how exosome-mediated preconditioning facilitates metastatic spread. While the SIRT1-IGF2BP2-v-ATPase axis regulates lysosomal function, this work also identifies it as a major mechanism of systemic communication in TNBC. By characterizing the exosomes controlled by this axis, I expect to identify key exosomal metabolites that drive PMN formation. These findings establish a framework to block metastasis, offering biomarkers and therapeutic targets to disrupt the signaling that promotes disease progression.