Inhibition of acetate metabolism enhances host anti-tumor immunity. Katelyn D. Miller, Katherine Pniewski, Seamus O’Connor, Sara Papp, & Zachary T. Schug. The Wistar Institute, Philadelphia, PA. Acquired resistance to anti-cancer therapy is an enormous challenge. One of the main factors contributing to therapy resistance is tumor hypoxia. The stress imposed by tumor hypoxia forces cancer cells to adapt in order to survive. These metabolically adapted cancer cells are often more invasive, more malignant, and more drug resistant. As a result, the cancer cells that emerge from hypoxic tumor regions are more likely to cause patient relapse. There is therefore a critical need to understand the mechanisms that promote the survival of cancer cells in stressful tumor microenvironments. We previously showed that the enzyme acetyl-CoA synthetase 2 (ACSS2) supports cancer cell metabolism in hypoxic and nutrient-depleted environments. ACSS2 endows cancer cells with the ability to use acetate as an alternative nutrient source to drive acetyl-CoA biosynthesis during stress and genetic silencing of ACSS2 inhibits human breast tumor growth in xenograft models. Given the important role of acetate metabolism in breast cancer we expanded upon our studies by using immunocompetent hosts and syngeneic mouse tumor models. Our results revealed a previously unknown role of ACSS2 in modulating host anti-tumor immunity. We found that ACSS2 deficient tumors are unable to grow when host immunity is intact. Depletion of host immunity (T cells) using genetic or pharmacological models rescues the growth of ACSS2 deficient tumors. Pharmacological inhibition of ACSS2 in tumors in vivo displayed gene signatures associated immune infiltration and activation within the tumor microenvironment. Moreover, ACSS2 deficient breast cancer cell lines show a marked susceptibility to T cell killing in vitro. Our current research demonstrates a novel role for acetate metabolism in supporting tumor extrinsic modulation of host anti-tumor immunity. Since activation of acetate metabolism via ACSS2 is a near universal hallmark of metabolically stressed cancer cells, targeting acetate metabolism represents an unrealized opportunity with significant upside for improving current therapeutic modalities in breast cancer.