Despite major strides in the early detection and treatment of breast cancer, metastatic disease remains a therapeutic challenge, resulting in over 40,000 deaths per year in the United States. Most breast cancers are the result of genetic mutations that lead to abnormal growth and invasive behavior of the tumor cells. Thus, therapies that reverse the effects of such mutations should be highly efficacious. However, this approach is often thwarted by the acquisition of drug resistance by the cancer. Genes encoding the PI3K (phosphatidylinositol 3-kinase) class of enzymes are frequently mutated in breast cancer, and drugs are now available that target these proteins. PI3Ks, however, are also important in regulating the immune response, leading to the concern that drugs that alter their activity may suppress the patient’s own anti-tumor defenses. These considerations led Vanderbilt Basic Sciences investigator Ann Richmond and her laboratory to embark on a careful study of the effects of a PI3K inhibitor on the growth of and immune response to breast cancer. Using mouse models of both murine and human breast cancers, they showed that PI3K inhibition led to a marked reduction in the rate of growth and metastasis of the tumors. In addition, they obtained the somewhat surprising result that PI3K inhibition augmented rather than suppressed the immune response to the cancers. In fact, genetic deletion of one PI3K isoform in the host mouse increased the immune response to a tumor that expressed the enzyme. Further studies showed that combining PI3K inhibition with an anti-PD-1 antibody (a therapy that blocks the ability of cancer cells to evade the immune system) led to a stronger response than could be obtained with either therapeutic approach alone. If these findings can be translated to human patients, they offer a promising new approach to the treatment of breast cancer. The work is published in the journal Clinical Cancer Research [J. Sai, et al. Clin. Cancer Res., published online December 21, DOI: 10.1158/1078-0432.CCR-16-2142].