SUMMARY Besides cell intrinsic damage to DNA, radiation (RT) can have systemic effects on the immune system. As such, recent evidence indicates that the efficacy of immune checkpoint blockade (ICB) for cancer can be improved by combination strategies that utilized both RT and ICB. However, our understanding of the pathways that RT utilizes to improve immune-mediated tumor response is limited. Moreover, not all cancer types may benefit from ICB with or without RT, likely necessitating additional maneuvers to enhance the efficacy of these treatments for many tumor types. Accumulating data point toward a role for pattern recognition receptors (PRRs) that are normally responsible for sensing pathogen-associated molecular patterns to activate the innate immune system and optimize immune response. RT may similarly promote the engagement of PRR pathways, resulting in activation of dendritic cells (DCs) that facilitate T cell cross-priming. The types of PRRs, the role of PRRs expressed in tumor cells, the nature of the ligands that engage PRRs, and how such events might converge on DC function after RT are not well understood. Therefore, to complement parallel clinical trials that test the combination of RT + αCTLA4 + αPD1 in patients with advanced cancer, this project seeks to investigate how RT mediates immunomodulatory effects through PRRs and how these signaling events get relayed to DCs to enhance the T cell repertoire. In order to expand the types of cancers that may benefit from RT + ICB, this proposal also examines how engagement of CD40 can non- redundantly activating DCs to further improve response particularly for poorly immunogenic tumors. Thus, by understanding the immunomodulatory mechanism of action of RT, its limitations, and ways to break through therapeutic barriers, our goal is to broaden the efficacy of RT + ICB to more patients in next generation clinical trials.