biostudies-literatureBalke-Want HParker Institute for Cancer ImmunotherapySaint Baldricks FoundationGerman Research FoundationMinisterium für Kultur und Wissenschaft des Landes Nordrhein-WestfalenMark Foundation For Cancer ResearchElse Kroner-Fresenius FoundationUniversity of Cologne Center for Molecular Medicine CologneNCI NIH HHSNational Institutes of HealthVirginia and D K Ludwig Fund for Cancer Research102549https://www.ebi.ac.uk/biostudies/studies/S-EPMC12866126biostudies-literatureUnknown7(1)Small cell lung cancer (SCLC), a highly lethal disease, limits T cell responses by downregulating major histocompatibility (MHC) class I molecules. Because chimeric antigen receptor (CAR) T cells are not MHC restricted, they may provide a powerful strategy against SCLC. However, few CAR targets for SCLC are known. Here, we show that B7-H3/CD276 is expressed in SCLC and thoracic SMARCA4-deficient undifferentiated tumors (UTs) that can clinicopathologically mimic SCLC. Thoracic SMARCA4-deficient UTs limit killing by B7-H3 CAR T cells via secretion of transforming growth factor β1 (TGF-β1). To overcome tumor-driven CAR T cell suppression, we knock in c-JUN alongside a B7-H3 CAR into the TRAC locus of primary human T cells utilizing CRISPR-Cas9. Non-viral c-JUN+B7-H3 CAR T cells show enhanced Cell reports. Medicinec-JUN enhances CRISPR knockin anti-B7-H3 CAR T cell function in small cell lung cancer and thoracic SMARCA4-deficient undifferentiated tumors.PMC12866126555464052R35 CA283888CAP36R35CA283888George JTunuguntla RHuang JBalke-Want HAsano KJiang QLiu XFowler CPatel SMackall CLChen YSage JKlysz DDRetherford AXu PDel Carmen Arenas MFeldman SAGkitsas-Long NKeerthi VHo KUllrich RHeitzeneder SSotillo EStahl DMalipatlolla MMaas Lfalsec-JUN enhances CRISPR knockin anti-B7-H3 CAR T cell function in small cell lung cancer and thoracic SMARCA4-deficient undifferentiated tumors.Small cell lung cancer (SCLC), a highly lethal disease, limits T cell responses by downregulating major histocompatibility (MHC) class I molecules. Because chimeric antigen receptor (CAR) T cells are not MHC restricted, they may provide a powerful strategy against SCLC. However, few CAR targets for SCLC are known. Here, we show that B7-H3/CD276 is expressed in SCLC and thoracic SMARCA4-deficient undifferentiated tumors (UTs) that can clinicopathologically mimic SCLC. Thoracic SMARCA4-deficient UTs limit killing by B7-H3 CAR T cells via secretion of transforming growth factor β1 (TGF-β1). To overcome tumor-driven CAR T cell suppression, we knock in c-JUN alongside a B7-H3 CAR into the TRAC locus of primary human T cells utilizing CRISPR-Cas9. Non-viral c-JUN+B7-H3 CAR T cells show enhanced 2026-01-01T00:00:00Z2026 Jan2026-07-15T06:17:38.157Z2026-06-30T03:21:47.41ZS-EPMC128661264156485710.1016/j.xcrm.2025.102549