Radiotherapy is a successful treatment modality for localized cancer. Our group has been exploring radiotherapy in combination with immunotherapy (radioimmunotherapy) to enhance systemic antitumor responses. Previously, we have shown that when local radiotherapy was combined with monoclonal antibodies (mAbs) (that enable T-cell responses by engaging costimulation [anti (α)-CD137]) and blocking coinhibition [α-PD-1], up to 100% of mice bearing established syngeneic AT-3 mammary tumors were cured, but single modality treatments were not curative. Here, we investigated the molecular mechanisms underlying responses to this radioimmunotherapy approach. We observed that inhibition of signaling through the mammalian target of rapamycin (mTOR) pathway during the first 10 days of treatment severely impaired the curative effect of radioimmunotherapy, at least in part by reducing MHC class I expression on tumor cells, reducing dendritic cell (DC) activation status and CD8(+) T-cell function. This data indicates that the efficacy of this type of radioimmunotherapy approach involves mTOR signaling and therefore, mTOR inhibitory drugs may impede the efficacy of similar radioimmunotherapy approaches in humans.