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CD103+ dendritic cells are critical for cross-presentation of tumor antigens. Here we have shown that during immunotherapy, large numbers of cells expressing CD103 arose in murine tumors via direct differentiation of Ly6c+ monocytic precursors. These Ly6c+CD103+ cells could derive from bone-marrow monocytic progenitors (cMoPs) or from peripheral cells present within the myeloid-derived suppressor cell (MDSC) population. Differentiation was controlled by inflammation-induced activation of the transcription factor p53, which drove upregulation of Batf3 and acquisition of the Ly6c+CD103+ phenotype. Mice with a targeted deletion of p53 in myeloid cells selectively lost the Ly6c+CD103+ population and became unable to respond to multiple forms of immunotherapy and immunogenic chemotherapy. Conversely, increasing p53 expression using a p53-agonist drug caused a sustained increase in Ly6c+CD103+ cells in tumors during immunotherapy, which markedly enhanced the efficacy and duration of response. Thus, p53-driven differentiation of Ly6c+CD103+ monocytic cells represents a potent and previously unrecognized target for immunotherapy.During tumor immunotherapy, CD103+ APCs can arise from the myeloid lineageThese CD11c+CD103+ APCs are Batf3 dependent but co-express monocytic markersDifferentiation of these cells from immature MDSC precursors is controlled by p53Selective ablation of this population results in profound defects in tumor immunityConventional CD103+ DCs are critical APCs for cross-presentation of tumor antigens. Sharma and colleagues show that a potent population of Batf3-dependent, CD103+ cross-presenting APCs can arise during tumor immunotherapy via direct differentiation of immature monocytic precursors present in the peripheral MDSC pool.