Abstract Body: Mice with increased macrophage expression of angiotensin converting enzyme (ACE), called ACE 10/10 mice, have a profound increase of macrophage function in response to diverse immune challenges including tumors, infection, atherosclerosis, and Alzheimer’s disease. ACE 10/10 macrophages are highly efficient in oxidative ATP generation, and they express increased amounts of peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor that controls lipid metabolism. To pinpoint the role of PPARα in increasing macrophage immune function, we used LysM-Cre-LoxP system to generate ACE 10/10 mice selectively lacking macrophage PPARα (A10-PPARα-Cre mice). This reduced macrophage fatty acid metabolism, reduced oxidative metabolism, and lowered macrophage intracellular ATP. Functionally, A10-PPARα-Cre macrophage are impaired in both adaptive and innate immunity. A10-PPARα-Cre mice have larger tumor growth of B16-F10 melanoma, less intratumor macrophages, reduced anti-tumor cytokines, and reduced generation of tumor antigen-specific CD8⁺ T cells. The mice also have a very attenuated anti-bacterial response to methicillin-resistant Staphylococcus aureus (MRSA) infection, with more severe MRSA tissue colonization in vivo. In addition, increasing ACE expression or adding a PPARα agonist to the human monocytic cell line THP-1 enhances tumor cell cytotoxicity, phagocytosis of bacteria, and bacterial killing. Thus, we find that elevated macrophage PPARα is absolutely required for the increased immunity of ACE 10/10 mice. This may indicate a pathway to increasing human immunity.