Fatty acid-binding proteins (FABP) are known central regulators of both metabolic and inflammatory pathways, but their role in tumor development remains largely unexplored. Here, we report that host expression of epidermal FABP (E-FABP) protects against mammary tumor growth. We find that E-FABP is highly expressed in macrophages, particularly in a specific subset, promoting their antitumor activity. In the tumor stroma, E-FABP-expressing tumor-associated macrophages (TAM) produce high levels of IFN-b through upregulation of lipid droplet formation in response to tumors. E-FABP-mediated IFN-b signaling can further enhance recruitment of tumoricidal effector cells, in particular natural killer cells, to the tumor stroma for antitumor activity. These findings identify E-FABP as a new protective factor to strengthen IFN-b responses against tumor growth.