{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T23:46:22Z","timestamp":1768520782362,"version":"3.49.0"},"posted":{"date-parts":[[2025,5,17]]},"group-title":"Immunology","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,17]],"date-time":"2025-05-17T00:00:00Z","timestamp":1747440000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NCI\/NIH","award":["R01CA215183"],"award-info":[{"award-number":["R01CA215183"]}]},{"name":"NCI\/NIH","award":["P30CA033572"],"award-info":[{"award-number":["P30CA033572"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>Despite advances in acute myeloid leukemia (AML) therapy, relapses remain challenging. While AML is radiation-sensitive, total body irradiation (TBI) causes organ toxicities and activates tolerogenic\/proangiogenic STAT3 signaling. CSI-2, a myeloid cell-targeted STAT3 inhibitor, promotes anti-leukemic immune responses but has limited efficacy against high disease burden. We investigated whether image-guided targeted marrow irradiation (TMI), which focuses radiation on leukemia sites while sparing critical organs, could synergize with CSI-2 to improve leukemia clearance and establish durable immunity.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Mice were intravenously engrafted with CMM-AML cells reaching 20\u201330% in bone marrow (BM) infiltration (moderate-to-high disease burden) before receiving IV-injections of CSI-2 (5mg\/kg) with or without TMI. Fluorescently labeled CSI-2 biodistribution was assessed using flow cytometry and quantitative multiphoton microscopy. Survival was monitored for 3\u20134 months before evaluating BM composition using flow cytometry and immunohistochemistry.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>TMI significantly improved vascular permeability and scavenger receptor\/TLR9-dependent uptake of CSI-2 by AML cells and leukemia-associated myeloid cells. Combined TMI\/CSI-2 treatment more effectively reduced high leukemia burden than CSI-2 alone, achieving &gt;80% survival at 120 days with increased CD8+ cytotoxic and CD4+ helper T cell infiltration. TMI\/CSI-2-treated mice were protected from AML rechallenge suggesting that they developed protective immune memory. In an aggressive MLL-AF9 AML model, TMI\/CSI-2 combination significantly extended survival compared to either monotherapy.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>TMI\/CSI-2 strategy represents a novel organ-sparing immunoradiotherapy that synergistically enhances leukemia clearance while promoting long-term protective immunity. These findings warrant further investigation of this strategy for high-burden or relapsed AML and provide the foundation for clinical translation.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.14.653587","type":"posted-content","created":{"date-parts":[[2025,5,18]],"date-time":"2025-05-18T01:37:42Z","timestamp":1747532262000},"source":"Crossref","is-referenced-by-count":1,"title":["Targeted Irradiation and STAT3 Inhibition Reprogram the AML Microenvironment and Extend Survival: Toward Translational Immunoradiotherapy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1087-6044","authenticated-orcid":false,"given":"Srideshikan Sargur","family":"Madabushi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jamison","family":"Brooks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darren","family":"Zuro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Lin","family":"Su","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Damian","family":"Kaniowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hemendra","family":"Ghimire","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji Eun","family":"Lim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amr Mohamed","family":"Hamed Abdelhamid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya-Huei","family":"Kuo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guido","family":"Marcucci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Wong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monzr","family":"Al Malki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Stein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcin","family":"Kortylewski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1394-3724","authenticated-orcid":false,"given":"Susanta","family":"Hui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025052013050749000_2025.05.14.653587v1.1","unstructured":"Society AC . Cancer Facts & Figures Atlanta, Ga 2019 [cited 2019 April 1]. Available from: https:\/\/www.cancer.org\/cancer\/acute-myeloid-leukemia\/about\/key-statistics.html#references."},{"key":"2025052013050749000_2025.05.14.653587v1.2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-05-018192"},{"key":"2025052013050749000_2025.05.14.653587v1.3","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-04-1623"},{"key":"2025052013050749000_2025.05.14.653587v1.4","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-12-399287"},{"key":"2025052013050749000_2025.05.14.653587v1.5","doi-asserted-by":"crossref","unstructured":"Rowe JM , Li X , Cassileth PA , Appelbaum FR , Schiffer CA , Wiernik PH , Litzow MR , Cripe LD , Lazarus HM , Paietta E. Very Poor Survival of Patients with AML Who Relapse after Achieving a First Complete Remission: The Eastern Cooperative Oncology Group Experience. Am Soc Hematology; 2005.","DOI":"10.1182\/blood.V106.11.546.546"},{"key":"2025052013050749000_2025.05.14.653587v1.6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.06.027"},{"key":"2025052013050749000_2025.05.14.653587v1.7","doi-asserted-by":"publisher","DOI":"10.1007\/s00066-006-1528-6"},{"key":"2025052013050749000_2025.05.14.653587v1.8","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V76.9.1867.1867"},{"key":"2025052013050749000_2025.05.14.653587v1.9","doi-asserted-by":"crossref","unstructured":"Stein A , Palmer J , Tsai N-C , Al Malki MM , Aldoss I , Ali H , Aribi A , Farol L , Karanes C , Khaled S. Phase I Trial of Total Marrow and Lymphoid Irradiation Transplant Conditioning in Patients with Relapsed\/Refractory Acute Leukemia. Biology of Blood and Marrow Transplantation. 2017.","DOI":"10.1016\/j.bbmt.2017.01.067"},{"key":"2025052013050749000_2025.05.14.653587v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtct.2025.01.178"},{"key":"2025052013050749000_2025.05.14.653587v1.11","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.28.8852"},{"key":"2025052013050749000_2025.05.14.653587v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2020.08.037"},{"key":"2025052013050749000_2025.05.14.653587v1.13","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.1045016"},{"key":"2025052013050749000_2025.05.14.653587v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(09)70082-8"},{"key":"2025052013050749000_2025.05.14.653587v1.15","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-1314"},{"key":"2025052013050749000_2025.05.14.653587v1.16","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.3MA1016-451RR"},{"key":"2025052013050749000_2025.05.14.653587v1.17","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201040979"},{"key":"2025052013050749000_2025.05.14.653587v1.18","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0810958105"},{"key":"2025052013050749000_2025.05.14.653587v1.19","doi-asserted-by":"publisher","DOI":"10.1172\/JCI60083"},{"key":"2025052013050749000_2025.05.14.653587v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2005.09.010"},{"key":"2025052013050749000_2025.05.14.653587v1.21","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1009659"},{"key":"2025052013050749000_2025.05.14.653587v1.22","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.1.252"},{"issue":"2","key":"2025052013050749000_2025.05.14.653587v1.23","doi-asserted-by":"crossref","first-page":"55","DOI":"10.4161\/jkst.20006","article-title":"STAT signaling in the pathogenesis and treatment of myeloid malignancies","volume":"1","year":"2012","journal-title":"Jak-Stat"},{"key":"2025052013050749000_2025.05.14.653587v1.24","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V88.7.2442.bloodjournal8872442"},{"key":"2025052013050749000_2025.05.14.653587v1.25","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V95.12.3765.012k50_3765_3770"},{"key":"2025052013050749000_2025.05.14.653587v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2013.04.002"},{"key":"2025052013050749000_2025.05.14.653587v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/nm1325"},{"key":"2025052013050749000_2025.05.14.653587v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3818"},{"key":"2025052013050749000_2025.05.14.653587v1.29","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-11-610592"},{"issue":"4","key":"2025052013050749000_2025.05.14.653587v1.30","doi-asserted-by":"crossref","first-page":"285","DOI":"10.4161\/jkst.22312","article-title":"Nucleic acid-based approaches to STAT inhibition","volume":"1","year":"2012","journal-title":"Jak-Stat"},{"key":"2025052013050749000_2025.05.14.653587v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2014.05.047"},{"key":"2025052013050749000_2025.05.14.653587v1.32","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aac5272"},{"key":"2025052013050749000_2025.05.14.653587v1.33","doi-asserted-by":"publisher","DOI":"10.3390\/ph6010085"},{"key":"2025052013050749000_2025.05.14.653587v1.34","doi-asserted-by":"publisher","DOI":"10.4161\/onci.27441"},{"key":"2025052013050749000_2025.05.14.653587v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1564"},{"key":"2025052013050749000_2025.05.14.653587v1.36","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-07-442590"},{"key":"2025052013050749000_2025.05.14.653587v1.37","doi-asserted-by":"crossref","unstructured":"Zhang B , Li L , Chen C , Stein AS , Ali H , Snyder DS , Lin A , Dorrance A , Swiderski P , Bhatia R , Perrotti D , Forman SJ, Y. K, Kortylewski M , Marcucci G. Knockdown (KD) of Mir-126 Expression Enhances Tyrosine Kinase Inhibitor (TKI)-Mediated Targeting of Chronic Myelogenous Leukemia (CML) Stem Cells. 57th Annual Meeting of American Society of Hematology. 2015. Epub 2015.","DOI":"10.1182\/blood.V126.23.51.51"},{"key":"2025052013050749000_2025.05.14.653587v1.38","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-07-517987"},{"key":"2025052013050749000_2025.05.14.653587v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexmp.2007.08.011"},{"key":"2025052013050749000_2025.05.14.653587v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2009.06.003"},{"key":"2025052013050749000_2025.05.14.653587v1.41","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-08-665604"},{"key":"2025052013050749000_2025.05.14.653587v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2010.301"},{"key":"2025052013050749000_2025.05.14.653587v1.43","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2019.246058"},{"key":"2025052013050749000_2025.05.14.653587v1.44","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-08-665604"},{"key":"2025052013050749000_2025.05.14.653587v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2013.06.007"},{"key":"2025052013050749000_2025.05.14.653587v1.46","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-6-225"},{"key":"2025052013050749000_2025.05.14.653587v1.47","doi-asserted-by":"publisher","DOI":"10.1667\/RR2773.1"},{"key":"2025052013050749000_2025.05.14.653587v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2005.12.014"},{"key":"2025052013050749000_2025.05.14.653587v1.49","doi-asserted-by":"publisher","DOI":"10.1038\/nm0797-730"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.05.14.653587","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T08:43:27Z","timestamp":1768466607000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.05.14.653587"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,17]]},"references-count":49,"URL":"https:\/\/doi.org\/10.1101\/2025.05.14.653587","relation":{},"subject":[],"published":{"date-parts":[[2025,5,17]]},"subtype":"preprint"}}