biostudies-literatureJagodinsky JCNCATS NIH HHSNIDCR NIH HHSNCI NIH HHSNIGMS NIH HHSNIH HHSeadk0642https://www.ebi.ac.uk/biostudies/studies/S-EPMC11522033biostudies-literatureUnknown16(765)Radiation therapy (RT) activates multiple immunologic effects in the tumor microenvironment (TME), with diverse dose-response relationships observed. We hypothesized that, in contrast with homogeneous RT, a heterogeneous RT dose would simultaneously optimize activation of multiple immunogenic effects in a single TME, resulting in a more effective antitumor immune response. Using high-dose-rate brachytherapy, we treated mice bearing syngeneic tumors with a single fraction of heterogeneous RT at a dose ranging from 2 to 30 gray. When combined with dual immune checkpoint inhibition in murine models, heterogeneous RT generated more potent antitumor responses in distant, nonirradiated tumors compared with any homogeneous dose. The antitumor effect after heterogeneous RT required CD4 and CD8 T cScience translational medicineIntratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade.PMC11522033T32 GM140935T32 GM007753P50 DE026787R01 GM102756P30 CA014520P01 CA250972F30 CA250263TL1 TR002375P50 CA278595R35 CA197078S10 OD023526DP5 OD024576U01 CA233102Vera JMSondel PMJin WJHavighurst TCGough MJAllawi RHKim KJagodinsky JCHarari PMShea AGClark PAMorris ZSOng IMChakravarthy INewton MASriramaneni RNCrittenden MRMiller JRfalseIntratumoral radiation dose heterogeneity augments antitumor immunity in mice and primes responses to checkpoint blockade.Radiation therapy (RT) activates multiple immunologic effects in the tumor microenvironment (TME), with diverse dose-response relationships observed. We hypothesized that, in contrast with homogeneous RT, a heterogeneous RT dose would simultaneously optimize activation of multiple immunogenic effects in a single TME, resulting in a more effective antitumor immune response. Using high-dose-rate brachytherapy, we treated mice bearing syngeneic tumors with a single fraction of heterogeneous RT at a dose ranging from 2 to 30 gray. When combined with dual immune checkpoint inhibition in murine models, heterogeneous RT generated more potent antitumor responses in distant, nonirradiated tumors compared with any homogeneous dose. The antitumor effect after heterogeneous RT required CD4 and CD8 T c2024-01-01T00:00:00Z2024 Sep2025-04-04T13:20:47.189Z2025-04-04T13:20:47.189ZS-EPMC115220333929280410.1126/scitranslmed.adk0642