{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T03:38:39Z","timestamp":1793504319495,"version":"4.5.0"},"posted":{"date-parts":[[2026,7,24]]},"group-title":"Cancer Biology","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100015326","name":"NIH Common Fund","doi-asserted-by":"crossref","award":["P01CA250972"],"award-info":[{"award-number":["P01CA250972"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100015326","name":"NIH Common Fund","doi-asserted-by":"crossref","award":["P50DE026787"],"award-info":[{"award-number":["P50DE026787"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Radiopharmaceutical therapies (RPT) deliver non-uniform radiation dose in tumors and the impact of this on response is poorly understood. Dose heterogeneity could engender treatment resistance in low dose regions, yet we hypothesize that a broader array of dose-dependent immuno-radiobiological mechanisms in tumor microenvironments (TME) and preservation of immune function in low-dose regions could promote adaptive anti-tumor immunity and response. In murine models, non-uniform lutetium-177 delivering &lt;2.5 Gy to &gt;20 Gy in a TME induced broader immunomodulatory effects and T cell-dependent survival improvement compared to more uniform distributions. Preserving low-dose regions promoted dendritic cell activation and TME infiltration of clonally expanded CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells. In three independent cohorts of patients with prostate cancer, heterogeneous tumor dose distribution strongly correlated with improved clinical outcomes. These findings defy expected radiobiological dose-response and define a novel mechanism of action for RPT, supporting clinical investigation of dose distribution for optimizing patient selection and personalized dosing.\n                <\/jats:p>","DOI":"10.64898\/2026.07.23.740178","type":"posted-content","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T13:50:13Z","timestamp":1784901013000},"source":"Crossref","is-referenced-by-count":1,"title":["Intratumoral dose heterogeneity promotes adaptive anti-tumor immunity and predicts clinical response to radiopharmaceutical therapy"],"prefix":"10.64898","author":[{"given":"Maya E.","family":"Takashima","sequence":"first","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0334-105X","authenticated-orcid":false,"given":"Ohyun","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5985-6052","authenticated-orcid":false,"given":"Zachary","family":"Ells","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Theranostics, Ahmanson Translational Theranostics Division, David Geffen School of Medicine, UCLA, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent R.","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Sawicki","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rene Welch","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin Hye","family":"Ahn","sequence":"additional","affiliation":[{"name":"Molecular Cancer Imaging Facility, Department of Imaging, Dana-Farber Cancer Institute, Boston, Massachusetts, USA"},{"name":"Department of Radiology, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meredith","family":"Hyun","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malick Bio","family":"Idrissou","sequence":"additional","affiliation":[{"name":"Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy J.","family":"Berg","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Lawless","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abby","family":"Besemer","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Bradshaw","sequence":"additional","affiliation":[{"name":"Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"},{"name":"Department of Radiology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Perlman","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wonjong","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Antonelli","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adedamola O","family":"Adeniyi","sequence":"additional","affiliation":[{"name":"Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Campbell Donnelly","family":"Haasch","sequence":"additional","affiliation":[{"name":"Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tessa","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ria","family":"Kumari","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0729-2179","authenticated-orcid":false,"given":"Reinier T.","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamey","family":"Weichert","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony P.","family":"Belanger","sequence":"additional","affiliation":[{"name":"Molecular Cancer Imaging Facility, Department of Imaging, Dana-Farber Cancer Institute, Boston, Massachusetts, USA"},{"name":"Department of Radiology, Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Ong","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Floberg","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Meyer","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Theranostics, Ahmanson Translational Theranostics Division, David Geffen School of Medicine, UCLA, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amar U","family":"Kishan","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, UCLA, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8839-4379","authenticated-orcid":false,"given":"Jeremie","family":"Calais","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Theranostics, Ahmanson Translational Theranostics Division, David Geffen School of Medicine, UCLA, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Bednarz","sequence":"additional","affiliation":[{"name":"Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary S.","family":"Morris","sequence":"additional","affiliation":[{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA 53705"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080212150924000_2026.07.23.740178v3.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-0246-1"},{"key":"2026080212150924000_2026.07.23.740178v3.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.09.014"},{"key":"2026080212150924000_2026.07.23.740178v3.3","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15618"},{"key":"2026080212150924000_2026.07.23.740178v3.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2017.08.016"},{"key":"2026080212150924000_2026.07.23.740178v3.5","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20052494"},{"key":"2026080212150924000_2026.07.23.740178v3.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.semradonc.2014.07.005"},{"key":"2026080212150924000_2026.07.23.740178v3.7","doi-asserted-by":"publisher","DOI":"10.7150\/thno.54881"},{"key":"2026080212150924000_2026.07.23.740178v3.8","doi-asserted-by":"publisher","DOI":"10.1088\/0031-9155\/38\/6\/001"},{"key":"2026080212150924000_2026.07.23.740178v3.9","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adk0642"},{"key":"2026080212150924000_2026.07.23.740178v3.10","doi-asserted-by":"publisher","DOI":"10.1186\/s13014-024-02514-6"},{"key":"2026080212150924000_2026.07.23.740178v3.11","doi-asserted-by":"publisher","DOI":"10.1667\/RR3819.1"},{"key":"2026080212150924000_2026.07.23.740178v3.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2018.10.009"},{"key":"2026080212150924000_2026.07.23.740178v3.13","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/63.5.1229"},{"key":"2026080212150924000_2026.07.23.740178v3.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.semradonc.2024.04.004"},{"key":"2026080212150924000_2026.07.23.740178v3.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2026.01.013"},{"key":"2026080212150924000_2026.07.23.740178v3.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctro.2019.10.004"},{"key":"2026080212150924000_2026.07.23.740178v3.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.brachy.2018.07.004"},{"key":"2026080212150924000_2026.07.23.740178v3.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-020-0073-9"},{"key":"2026080212150924000_2026.07.23.740178v3.19","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.121.262750"},{"key":"2026080212150924000_2026.07.23.740178v3.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2022.08.010"},{"key":"2026080212150924000_2026.07.23.740178v3.21","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2107322"},{"key":"2026080212150924000_2026.07.23.740178v3.22","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1607427"},{"key":"2026080212150924000_2026.07.23.740178v3.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2020.12.002"},{"key":"2026080212150924000_2026.07.23.740178v3.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.semradonc.2023.03.011"},{"key":"2026080212150924000_2026.07.23.740178v3.25","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.123.266345"},{"key":"2026080212150924000_2026.07.23.740178v3.26","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.118.224808"},{"key":"2026080212150924000_2026.07.23.740178v3.27","doi-asserted-by":"publisher","DOI":"10.1089\/cbr.2018.2451"},{"key":"2026080212150924000_2026.07.23.740178v3.28","doi-asserted-by":"publisher","DOI":"10.1118\/1.4921997"},{"key":"2026080212150924000_2026.07.23.740178v3.29","doi-asserted-by":"publisher","DOI":"10.1667\/RADE-20-00065.1"},{"key":"2026080212150924000_2026.07.23.740178v3.30","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-0003"},{"key":"2026080212150924000_2026.07.23.740178v3.31","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abb3631"},{"key":"2026080212150924000_2026.07.23.740178v3.32","doi-asserted-by":"publisher","DOI":"10.3109\/07357907.2012.700987"},{"key":"2026080212150924000_2026.07.23.740178v3.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2019.08.047"},{"key":"2026080212150924000_2026.07.23.740178v3.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-41301-3"},{"key":"2026080212150924000_2026.07.23.740178v3.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2018.01.003"},{"key":"2026080212150924000_2026.07.23.740178v3.36","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.01241"},{"key":"2026080212150924000_2026.07.23.740178v3.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-023-00990-6"},{"key":"2026080212150924000_2026.07.23.740178v3.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113556"},{"key":"2026080212150924000_2026.07.23.740178v3.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.12.012"},{"key":"2026080212150924000_2026.07.23.740178v3.40","doi-asserted-by":"publisher","DOI":"10.1200\/JCO-25-01553"},{"key":"2026080212150924000_2026.07.23.740178v3.41","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.125.271467"},{"key":"2026080212150924000_2026.07.23.740178v3.42","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-024-06764-0"},{"key":"2026080212150924000_2026.07.23.740178v3.43","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34676-w"},{"key":"2026080212150924000_2026.07.23.740178v3.44","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31941-w"},{"key":"2026080212150924000_2026.07.23.740178v3.45","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2023.41.16_suppl.5046"},{"key":"2026080212150924000_2026.07.23.740178v3.46","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19917-0"},{"key":"2026080212150924000_2026.07.23.740178v3.47","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.591139"},{"key":"2026080212150924000_2026.07.23.740178v3.48","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3364"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.07.23.740178","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T19:15:21Z","timestamp":1785698121000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.07.23.740178"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,24]]},"references-count":48,"URL":"https:\/\/doi.org\/10.64898\/2026.07.23.740178","relation":{},"subject":[],"published":{"date-parts":[[2026,7,24]]},"subtype":"preprint"}}