Antigen generation occurs upon tumor cell death due to RT and neoantigen (pink) uptake by cross-priming dendritic cells (cpDCs). Type I inflammation is triggered with associated cytokine secretion (type I interferon, blue), which upregulates MHC class I molecules on cpDCs. These cells migrate to lymph nodes from the site of the primary tumor and present tumor-associated antigens to naive T cells. This gives rise to a population of tumor-reactive CD4⁺ and CD8⁺ T cells, as depicted, and these cells are released systemically. At the primary tumor mass, tumor-reactive T cells are the main effectors carrying out the abscopal effect. This includes release of cytotoxic molecules (green) by CD8⁺ T cells upon recognition of tumor antigen (pink). This is aided by costimulatory release of cytokines such as IL-2 by CD4⁺ T cells upon antigen recognition, which promote T cell proliferation and effector function. M1 macrophages contribute to tumor cell killing by direct phagocytosis and secretion of type I inflammatory cytokines (purple). Importantly, given that immune cells are primed in lymph nodes and released systemically, these activities also take place at distal metastases where tumors exhibit the same antigen, which gives rise to the abscopal effect.