Abstract The primary goal of this project is to enhance the efficacy of immunotherapy against metastatic colorectal cancer (mCRC) by activating the peroxisome proliferator-activated receptor delta (PPARδ)-Carnitine palmitoyltransferase 1a (Cpt1a) axis in CD8+ T cells. Colorectal cancer (CRC) is among the deadliest cancers worldwide, with rising incidence and mortality in younger populations. Particularly, mCRC patients, predominantly of the microsatellite stable (MSS) subtype, show poor responsiveness to current immunotherapies due to the immunosuppressive tumor microenvironment and low mutation burden that associates with limited immunogenicity. This creates an urgent need for innovative approaches to boost the immunogenicity and improve treatment outcomes. Our preliminary studies highlight the role of PPARδ, a lipid-sensing transcription factor, in modulating the metabolic fitness of CD8+ T cells within the tumor microenvironment, thereby enhancing their immunogenic potential against mCRC. We found that by promoting mitochondrial fatty acid oxidation (FAO) through the PPARδ-Cpt1a axis, we could significantly augment the efficacy of existing immunotherapies. The roles of PPARδ and FAO in tumorigenesis and immunity are controversial due to lack of cell type-specific genetic loss-of-function and gain-of-function models. We hypothesize that the metabolic competition between cancer cells and the immune system is a critical determinant of immune cell fitness against cancer. By activating PPARδ in CD8+ T cells, we aim to tip this balance to enhance immune cell function and thus improve the anti-tumor efficacy of immunotherapies in mCRC. To achieve our goal, we propose three synergistic aims. First, we will delineate the specific mechanisms by which PPARδ activation enhances the anti-tumor activity of CD8+ T cells in the context of MSS mCRC, focusing on their anti-metastatic function and the underlying epigenetic alterations. Second, we will elucidate the role of Cpt1a-me