{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T09:17:43Z","timestamp":1794129463916,"version":"4.8.0"},"reference-count":85,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"CureStartsNow Foundation"},{"name":"ChadTough Defeat DIPG Foundation"},{"DOI":"10.13039\/100015612","name":"CancerFree KIDS","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015612","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"NINDS","doi-asserted-by":"publisher","award":["R01NS140460"],"award-info":[{"award-number":["R01NS140460"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"NINDS","doi-asserted-by":"publisher","award":["R01NS142389"],"award-info":[{"award-number":["R01NS142389"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Diffuse middle glioma (DMG or DIPG) is a fatal pediatric brain tumor. Although chimeric antigen receptor (CAR) T-cell therapy shows promise, clinical outcomes remain inconsistent due to premature exhaustion, underscoring a critical need to improve CAR-T persistence. A major barrier to CAR-T efficacy is antigen-independent tonic signaling, yet the extent to which tonic signaling shapes CAR-T durability and clinical outcomes, particularly in DMG, remains incompletely defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using a clinically investigated B7-H3 MGA271-based CAR as a reference platform, we generated alternative B7-H3 CARs incorporating either a human codon-optimized 376.96 (B7H3.BC) or Hu8H9 scFv antigen-binding domain to systematically assess scFv-dependent effects on tonic signaling and therapeutic efficacy. CAR-T cells were evaluated using integrated in vitro and in vivo functional assays, alongside multi-omics profiling and computational modeling. We further derived a tonic signaling-associated gene signature and evaluated its predictive performance across independent clinical datasets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>B7H3.BC CAR-T cells exhibit markedly restrained tonic signaling compared with MGA271- and Hu8H9-based counterparts, accompanied by superior antitumor activity and enhanced persistence across patient-derived DMG cells. Integrated multi-omics and single-cell profiling further identified a tonic signaling-associated gene signature that outperforms conventional T-cell exhaustion signatures in predicting therapeutic efficacy across multiple clinical trials, including DMG and other tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings establish that scFv-dependent modulation of tonic signaling critically governs CAR-T persistence and antitumor efficacy in DMG. By linking CAR design to transcriptional and epigenetic programs, our study provides a principle-based and predictive framework to inform rational CAR engineering and improve therapeutic outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/neuonc\/noag205","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T04:19:51Z","timestamp":1788236391000},"source":"Crossref","is-referenced-by-count":1,"title":["A CAR-T tonic signaling code predicts anti-tumor efficacy in diffuse midline glioma"],"prefix":"10.1093","author":[{"given":"Bing","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Pediatrics, O\u2019Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham (UAB) , Birmingham, Alabama,","place":["USA"]},{"name":"Department of Cancer Biology, University of Cincinnati College of Medicine , Cincinnati, Ohio,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5366-0143","authenticated-orcid":false,"given":"Xiaowen","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, O\u2019Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham (UAB) , Birmingham, Alabama,","place":["USA"]},{"name":"Division of Pharmaceutical Sciences, James L. 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