Accumulating pre-clinical and clinical evidence supports the ability of focal tumor radiotherapy (RT) to enhance responses to immune checkpoint blockade (ICB) therapy. However, the requirements for the expansion of the RT-induced local immune reaction into efficient systemic antitumor immunity mediating abscopal responses remain incompletely understood. Recent data suggest that radiation-induced viral mimicry is a key mechanism for in situ immunization by RT. The accumulation of cytosolic DNA that follows radiation-induced DNA damage stimulates type I interferon (IFN-I) via the cGAS/STING pathway, thus generating signals that promote the cross-presentation of tumor antigens by dendritic cells (DCs) to CD8 T cells. In addition, the rapid and profound changes in the trascriptome associated with DNA damage repair responses modulate the repertoire of neoepitopes presented by MHC molecules, increasing tumor antigenicity. We are currently investigating the characteristics of an effective anti-tumor T cell response generated by RT and ICB in mice as well as patients. Recent data from single cell analysis in mice indicate that radiation promotes a diversification and expansion of the T cell receptor (TCR) repertoire of tumor-infiltrating T cells (TILs). A subset of polyfunctional CD69+ CD8 T cells that express interferon-g and TNFa emerges only in the tumor of mice treated with RT and CTLA-4 blockade in combination but not as single treatments. Additionally, we have found that T cells with the same Ag-specificity exist at different transcriptional states in the tumor. Overall, these results support the notion that RT promotes T cell priming but is insufficient to drive the expansion and functional differentiation of T cell phenotypes necessary for tumor rejection. They also support the hypothesis that tumor control results from combined activity of a range of differentiation states within the T cell compartment and provide new insights into the synergy between RT anti-CTLA-4 that we have observed in both mice and patients.