Abstract Breast cancers (BC) remain the most lethal malignancies amongst women worldwide and the second leading cause of cancer-related mortality in the US. Subtype heterogeneity and aggressive metastatic potential are believed to be the major contributors of these outcomes. Although the standard targeted therapies have shown some efficacy against classically overexpressed BC receptors (i.e. estrogen/progesterone receptors, ER+/PR+ and human epidermal growth factor receptor 2, HER2+), BC lacking all three of these receptors (triple-negative, TNBC) are notoriously aggressive, difficult-to-treat, and metastatic. Current treatment options for TNBC include neoadjuvant chemotherapy and surgery which can have limited utility in advanced metastatic disease. A recent surge of interest on the role of tumor-associated inflammation on metastatic progression lead to the observation that the degree of inflammation-driven tumorigenesis tends to correlate with increased levels of cell-free DNA (cfDNA) in cancer patient sera. Such observations prompted our lab to explore the use of nucleic-acid scavengers (NASs) as a means of blocking the pro-inflammatory signals elicited by these cfDNA to innate immune sensors such as TLRs. In this proposal, I aim to (1) define the effects of NAS treatment on innate immune system signaling in BC using in vitro and ex vivo models, (2) elucidate the mechanism by which these NAS work in the BC setting using novel molecular tools developed in the lab, and (3) evaluate how these molecules limit metastases in an immune-competent in vivo model. Thus, I propose mechanistic studies to define how NAS ameliorate aberrant immune cell activation, and in vivo validation studies to gain a better understanding of how these molecules behave in a clinically relevant disease model. Successful completion of this proposal will enhance basic understanding of metastatic progression and its interplay with the immune system, and uncover principles that may aid in the development efforts of anti-metastatic therapies to improve TNBC patient outcomes. !