The molecular mechanisms that promote resistance to T cell–mediated immunotherapy in patients with melanoma remain unclear. Peng and colleagues found that loss of PTEN in melanoma cells suppressed T cell–driven antitumor responses both in vitro and in vivo. Consistent with this finding, PTEN-negative melanomas exhibited impaired infiltration and function of CD8⁺ T cells and decreased sensitivity to immunotherapy. This immune-suppressive effect was mediated by upregulation of the expression of immunosuppressive cytokines and inhibition of autophagy in the absence of PTEN. Selective inhibition of the PI3Kβ isoform restored the sensitivity of PTEN-null melanoma cells to T cell–mediated immunotherapy. These results support the notion that loss of PTEN drives resistance to immunotherapy in melanoma and suggest that combined treatment with PI3K–AKT inhibitors may enhance the clinical efficacy of immunotherapies. For details, please see the article by Peng and colleagues on page 202.