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Melanoma tumors are highly immunogenic, making them an attractive target for immunotherapy. However, many patients do not mount robust clinical responses to targeted therapies, which is attributable, at least in part, to suppression of immune responses by tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Using a human in vitro culture system, we now show that the synthetic triterpenoid CDDO-Me enhances immune activation by reprogramming macrophages from immuno-suppressive to immuno-stimulatory. CDDO-Me treatment inhibits surface marker expression of CD16 and CD163 and significantly reduces production of CCL2 and IL-6 in macrophages. These studies also demonstrate that CDDO-Me effects on TAM activation are enhanced when macrophages are tri-cultured with autologous activated T cells and BRAFV600Emutant cells. Because CDDO-Me dramatically attenuates secretion of CCL2, we hypothesize that CDDO-Me may enhance melanoma patient response to additional immunotherapies, including BRAF inhibition. Approximately 50% of advanced melanomas harbor activating BRAFV600Emutations, and BRAF inhibitors have consistently shown anti-tumor responses in patients with BRAFV600Emutant melanoma. However, the duration of the response has been limited due to the development of acquired resistance, which occurs because of myeloid recruitment driven by CCL2. Current studies are focused on assessing the efficacy of combination CDDO-Me/BRAF inhibition. Collectively, these studies suggest that the redirection of immuno-suppressive myeloid cell activation may provide both a direct means of inhibiting melanoma growth and may enhance the efficacy of additional targeted immunotherapies.