Epidemiologic studies and multiple preclinical studies suggest dietary fish oil has the potential to delay prostate cancer progression. A prospective randomized pre-prostatectomy trial conducted by our group found that consuming a fish oil (omega-3) supplemented diet resulted in lower proliferation of prostate cancer epithelium as measured by the Ki-67 index, and decreased Cell Cycle Progression (CCP) Score as compared to a control Western diet. Both Ki-67 and the CCP Score are associated with prostate cancer progression and mortality, suggesting potential benefits of consuming a fish oil supplemented diet for prostate cancer patients. In studies with immunocompetent GPR120 knockout (KO) mice, we recently demonstrated that GPR120, a g-protein coupled receptor important in the transport of long chain polyunsaturated fatty acids, is required in the host for the anti-cancer activity of fish oil. Immune suppressive tumor associated macrophages with M2-like characteristics have been associated with prostate cancer progression and poor prognosis. We also found that fish oil inhibits the function of M2-like tumor-associated macrophages, and this effect was reversed in the GPR120 KO mouse. Based on these findings, we hypothesize that a fish oil supplemented diet will delay the progression of prostate cancer through GPR120 dependent effects on the tumor microenvironment. The Aims of our proposal are: Aim 1. Determine if dietary omega-3 (ω-3) fatty acids act through GPR120 to inhibit prostate cancer in a transgenic mouse model and study underlying mechanisms related to M2 macrophage function. Aim 2. Determine if GPR120 dependent host-derived bone marrow cells and myeloid lineage cells are essential for the anticancer effects of dietary ω-3 FAs. Aim 3. Identify biomarkers in baseline prostate biopsy tissue that predict responsiveness to a fish oil based dietary intervention by examining prostate biopsy tissue obtained from an ongoing active surveillance trial in men receiving a fish oil supplemented diet (ω-6: ω-3 ratio of 3:1). We will accomplish these aims through a series of mechanistic studies using GPR120 knockout and transgenic mouse models fed diets varying in ω-3 and ω-6 fatty acid content, and studies on prostate biopsy tissue from a Phase II, dietary intervention, active surveillance trial we are conducting in men with prostate cancer. Significance: Our proposal sets a new direction for a precision medicine approach for selecting patients more likely to be responsive to dietary modification based on GPR120 status. By studying the underlying biology of fish oil anticancer effects through GPR120 and tumor associated macrophages/immune cells, we are establishing a new field of study, nutritional immunotherapy, that may ultimately lead to innovative nutritional therapies for our patients with prostate cancer. Our multidisciplinary team of investigators with a longstanding history of successful collaborations is uniquely suited to achieve our stated goals.