{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T18:14:48Z","timestamp":1779387288769,"version":"3.53.1"},"reference-count":71,"publisher":"American Society for Clinical Investigation","issue":"10","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008065","name":"Georgia Research Alliance","doi-asserted-by":"crossref","award":["GRA VL20.C7"],"award-info":[{"award-number":["GRA VL20.C7"]}],"id":[{"id":"10.13039\/100008065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01DE026941,P30CA138292"],"award-info":[{"award-number":["R01DE026941,P30CA138292"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,22]]},"abstract":"<jats:p>\n                    We investigated whether destroying malignant cells and the associated tumor microenvironment (TME) by focal gene therapy would broaden immune checkpoint inhibitor (ICI) effectiveness. We show that ICI antitumor activity against syngeneic (murine) triple-negative breast cancer (TNBC) was augmented when a therapeutic transgene (purine nucleoside phosphorylase\n                    <jats:italic>,<\/jats:italic>\n                    referred to here as\n                    <jats:italic>E<\/jats:italic>\n                    .\n                    <jats:italic>coli<\/jats:italic>\n                    PNP) was used to cleave fludarabine (2-fluoro-arabinofuranosyl adenine) to the anticancer purine base, 2-fluoroadenine (F-Ade). We also established strong repression of anatomically distant, non-PNP-expressing tumors being treated by the same strategy. TNBC cytoreduction was associated with decreased intratumoral PD1\n                    <jats:sup>+<\/jats:sup>\n                    Tregs, increased granzyme B\n                    <jats:sup>+<\/jats:sup>\n                    NK cells, elevated MKI67\n                    <jats:sup>+<\/jats:sup>\n                    T8 cells, and rapid immune clearance. Because F-Ade works by a mechanism that destroys quiescent neoplastic and supporting cells in the microenvironment, and since resistance to ICIs depends upon an intact TME, tumor killing by this approach offers a means to sensitize refractory malignancies to immune ablation and points to broad applicability against numerous cancer subtypes.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.194142","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T18:00:52Z","timestamp":1779386452000},"source":"Crossref","is-referenced-by-count":0,"title":["Broadening activity of checkpoint blockade agents by intratumoral nucleoside cleavage"],"prefix":"10.1172","volume":"11","author":[{"given":"Regina","family":"Rab","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Asthma, Cystic Fibrosis, and Sleep, Department of Pediatrics, Emory University School of Medicine and Children\u2019s Healthcare of Atlanta, Atlanta, Georgia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4719-1855","authenticated-orcid":true,"given":"Jeong S.","family":"Hong","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Asthma, Cystic Fibrosis, and Sleep, Department of Pediatrics, Emory University School of Medicine and Children\u2019s Healthcare of Atlanta, Atlanta, Georgia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan L.C.","family":"Kinney","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology \u2013 Head and Neck Surgery, and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole C.","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology \u2013 Head and Neck Surgery, and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William B.","family":"Parker","sequence":"additional","affiliation":[{"name":"PNP Therapeutics Inc., Birmingham, Alabama, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrianna","family":"Westbrook","sequence":"additional","affiliation":[{"name":"Pediatric Biostatistics Core, Department of Pediatrics, Emory University, Atlanta, Georgia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey B.","family":"Bennion","sequence":"additional","affiliation":[{"name":"Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6736-4421","authenticated-orcid":true,"given":"Mandy L.","family":"Ford","sequence":"additional","affiliation":[{"name":"Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas H.","family":"Weitzel","sequence":"additional","affiliation":[{"name":"Charles River Laboratories and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula L.","family":"Miliani de Marval","sequence":"additional","affiliation":[{"name":"SpringWorks Therapeutics, Research Triangle Park, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric J.","family":"Sorscher","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Asthma, Cystic Fibrosis, and Sleep, Department of Pediatrics, Emory University School of Medicine and Children\u2019s Healthcare of Atlanta, Atlanta, Georgia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Ehrhardt","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Asthma, Cystic Fibrosis, and Sleep, Department of Pediatrics, Emory University School of Medicine and Children\u2019s Healthcare of Atlanta, Atlanta, Georgia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-024-00883-1"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-024-00761-z"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1126\/science.adq1717"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.09.020"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-023-00973-8"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-01136-2"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.35713\/aic.v2.i3.25"},{"key":"B8","unstructured":"GlobeNewswire. 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