Abstract We recently reported that breast cancer cells induce the generation of a regulatory B-cell subset (tumor-evoked Bregs, tBregs) from naïve B cells to promote cancer escape and lung metastasis. One of the mechanisms involved is the ability of tBregs to promote Treg expansion. Thus, aiming to understand this process we screened several compounds that could block the generation of tBregs. We found that resveratrol (RSV), a natural polyphenol with chemopreventice properties, specifically blocked the ability of cancer cells to convert B cells into tBregs. This blockage results in the inability of tBregs to suppress T-cell proliferation and promote tumor growth and lung metastasis. The molecular mechanism of this process is that RSV targeted and inactivated PPAR-alpha, a nuclear receptor implicated in several processes such as lipid metabolism, proliferation or differentiation. Thus, our data show the importance of PPAR-alpha in tBreg generation, and one mechanism of the anti-tumor properties of RSV is the inactivation of this pathway in tBregs. This work was entirely supported by the Intramural Research Program of the National Institutes of Health.