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Through single-cell RNA sequencing analysis of tumor-infiltrating T cells from patients with glioma, NR4A family genes were identified as closely associated with T cell exhaustion and were coexpressed with dysfunctional genes\n            <jats:italic toggle=\"yes\">HAVCR2<\/jats:italic>\n            and\n            <jats:italic toggle=\"yes\">TIGIT<\/jats:italic>\n            . Notably, CAR T cells with\n            <jats:italic toggle=\"yes\">NR4A3<\/jats:italic>\n            knockdown exhibited enhanced cytotoxic activity against tumors, leading to improved tumor clearance and prolonged survival in vivo. However, the promoted antiexhausted phenotype diminished with prolonged tumor burden. This decline in T cell function correlates with the compensatory down-regulation of\n            <jats:italic toggle=\"yes\">FOS<\/jats:italic>\n            induced by chronic antigen exposure following\n            <jats:italic toggle=\"yes\">NR4A3<\/jats:italic>\n            knockdown. Overexpressing\n            <jats:italic toggle=\"yes\">FOS<\/jats:italic>\n            alongside\n            <jats:italic toggle=\"yes\">NR4A3<\/jats:italic>\n            knockdown robustly boosted the antitumor responses of CAR T cells by skewing their phenotypes and transcriptional profiles away from exhaustion and toward increased effector function. These findings offer a promising strategy for the clinical modification of CAR T cell therapy.\n          <\/jats:p>","DOI":"10.1126\/sciadv.adw3571","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T17:58:56Z","timestamp":1760723936000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":14,"title":["Enhanced\n            <i>FOS<\/i>\n            expression improves tumor clearance and resists exhaustion in NR4A3-deficient CAR T cells under chronic antigen exposure"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7172-7560","authenticated-orcid":true,"given":"Peidi","family":"Yin","sequence":"first","affiliation":[{"name":"Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, P.R. China."},{"name":"Institute of Pathology, Medical Research Center for Glioma, Southwest Cancer Center, the First Affiliated Hospital (Southwest Hospital) and School of Basic Medical Sciences, Army Medical University (Third Military Medical University), and the Key Laboratory of Tumor Immunopathology, the Ministry of Education (Third Military Medical University), Chongqing 400038, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1421-8193","authenticated-orcid":true,"given":"Jigui","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Medical Research Center for Glioma, Southwest Cancer Center, the First Affiliated Hospital (Southwest Hospital) and School of Basic Medical Sciences, Army Medical University (Third Military Medical University), and the Key Laboratory of Tumor Immunopathology, the Ministry of Education (Third Military Medical University), Chongqing 400038, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5026-419X","authenticated-orcid":true,"given":"Yiyang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, P.R. China."},{"name":"Institute of Pathology, Medical Research Center for Glioma, Southwest Cancer Center, the First Affiliated Hospital (Southwest Hospital) and School of Basic Medical Sciences, Army Medical University (Third Military Medical University), and the Key Laboratory of Tumor Immunopathology, the Ministry of Education (Third Military Medical University), Chongqing 400038, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linhong","family":"Han","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Medical Research Center for Glioma, Southwest Cancer Center, the First Affiliated Hospital (Southwest Hospital) and School of Basic Medical Sciences, Army Medical University (Third Military Medical University), and the Key Laboratory of Tumor Immunopathology, the Ministry of Education (Third Military Medical University), Chongqing 400038, China."},{"name":"Intelligent Pathology Institute and Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8131-3550","authenticated-orcid":true,"given":"Tianchen","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Hematology &amp; Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4584-3103","authenticated-orcid":true,"given":"Haofei","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Medical Research Center for Glioma, Southwest Cancer Center, the First Affiliated Hospital (Southwest Hospital) and School of Basic Medical Sciences, Army Medical University (Third Military Medical University), and the Key Laboratory of Tumor Immunopathology, the Ministry of Education (Third Military Medical University), Chongqing 400038, China."},{"name":"Organoid Innovation Center, CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, P.R. 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