{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T18:10:05Z","timestamp":1788891005559,"version":"build-2803163510"},"reference-count":45,"publisher":"National Academy of Sciences","issue":"37","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82388201"],"award-info":[{"award-number":["82388201"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32525028"],"award-info":[{"award-number":["32525028"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences","award":["2025-I2M-XHZY-019"],"award-info":[{"award-number":["2025-I2M-XHZY-019"]}]},{"name":"Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences","award":["2024-I2M-ZD-005"],"award-info":[{"award-number":["2024-I2M-ZD-005"]}]},{"name":"Suzhou1114 Key Laboratory Program","award":["SZS2023005"],"award-info":[{"award-number":["SZS2023005"]}]},{"name":"Basic Research Program of Jiangsu","award":["BK20250003"],"award-info":[{"award-number":["BK20250003"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,15]]},"abstract":"<jats:p>\n                    T cell dysfunction critically limits the efficacy of T cell\u2013based immunotherapies in solid tumors, yet the intrinsic regulators of T cell dysfunction remain incompletely understood. Through an in vivo genome-wide CRISPR screen in tumor-infiltrating CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, we identified Forkhead Box R1 (FOXR1) as a potent transcriptional suppressor of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell effector functions. Genetic ablation of FOXR1 significantly enhanced cytokine production and cytotoxic capacity in both murine and human CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, whereas its overexpression impaired T cell activation and effector molecule expression. Mechanistically, multiomics integration of RNA-seq, CUT&amp;Tag-seq, and ATAC-seq revealed that FOXR1 binds directly to promoter regions of key effector genes, including\n                    <jats:italic toggle=\"yes\">IL2, GZMB,<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">PRF1<\/jats:italic>\n                    , and represses their expression. Importantly, FOXR1 deletion in human anti-CD19 CAR T cells improved their efficacy against solid tumors, demonstrating that FOXR1 is a checkpoint of T cell effector function and targeting FOXR1 is a promising strategy to enhance CAR T cell efficacy against solid tumors.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2534362123","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T17:47:37Z","timestamp":1788889657000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["In vivo genome-wide CRISPR screens identify FOXR1 as a suppressor of CD8\n                    <sup>+<\/sup>\n                    T cell antitumor immunity"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7746-440X","authenticated-orcid":false,"given":"Xue","family":"Yang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02drdmm93","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Beijing, China"]},{"id":[{"id":"https:\/\/ror.org\/02drdmm93","id-type":"ROR","asserted-by":"publisher"}],"name":"National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Ouyang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02drdmm93","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of 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Yang In vivo genome-wide CRISPR screens identify FOXR1 as a suppressor of CD8+ T cell anti-tumor immunity [RNA-Seq 1]. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE311128. Deposited 24 November 2025."},{"key":"e_1_3_4_42_2","unstructured":"X. Yang In vivo genome-wide CRISPR screens identify FOXR1 as a suppressor of CD8+ T cell anti-tumor immunity [RNA-Seq 2]. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE311131. Deposited 24 November 2025."},{"key":"e_1_3_4_43_2","unstructured":"X. Yang In vivo genome-wide CRISPR screens identify FOXR1 as a suppressor of CD8+ T cell anti-tumor immunity [CRISPR screen]. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE311125. Deposited 24 November 2025."},{"key":"e_1_3_4_44_2","unstructured":"X. Yang In vivo genome-wide CRISPR screens identify FOXR1 as a suppressor of CD8+ T cell anti-tumor immunity [CUT&Tag]. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE329850. Deposited 4 May 2026."},{"key":"e_1_3_4_45_2","unstructured":"X. Yang In vivo genome-wide CRISPR screens identify FOXR1 as a suppressor of CD8+ T cell anti-tumor immunity [ATAC-Seq]. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE329849. Deposited 4 May 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2534362123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T17:48:33Z","timestamp":1788889713000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2534362123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,8]]},"references-count":45,"journal-issue":{"issue":"37","published-print":{"date-parts":[[2026,9,15]]}},"alternative-id":["10.1073\/pnas.2534362123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2534362123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,8]]},"assertion":[{"value":"2025-11-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2534362123"}}