{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T09:11:11Z","timestamp":1793869871109,"version":"4.6.1"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"8010","license":[{"start":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T00:00:00Z","timestamp":1712707200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T00:00:00Z","timestamp":1712707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"published-print":{"date-parts":[[2024,5,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma\n                    <jats:sup>1\u20134<\/jats:sup>\n                    , but the efficacy of CAR T cell therapy in solid tumours has been limited\n                    <jats:sup>5<\/jats:sup>\n                    . This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more \u2018stem-like\u2019 phenotype and increased mitochondrial mass\n                    <jats:sup>6\u20138<\/jats:sup>\n                    . We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours.\n                  <\/jats:p>","DOI":"10.1038\/s41586-024-07242-1","type":"journal-article","created":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T12:01:48Z","timestamp":1712750508000},"page":"201-210","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":269,"title":["FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy"],"prefix":"10.1038","volume":"629","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5942-8592","authenticated-orcid":false,"given":"Jack D.","family":"Chan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3731-6204","authenticated-orcid":false,"given":"Christina M.","family":"Scheffler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6510-5696","authenticated-orcid":false,"given":"Isabelle","family":"Munoz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4634-7600","authenticated-orcid":false,"given":"Kevin","family":"Sek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel N.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2262-7069","authenticated-orcid":false,"given":"Yu-Kuan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5009-9895","authenticated-orcid":false,"given":"Kah Min","family":"Yap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole Y. L.","family":"Saw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmine","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda X. Y.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheok Weng","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7191-3948","authenticated-orcid":false,"given":"Emily B.","family":"Derrick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3903-166X","authenticated-orcid":false,"given":"Kirsten L.","family":"Todd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6454-8704","authenticated-orcid":false,"given":"Junming","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phoebe A.","family":"Dunbar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thang X.","family":"Hoang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3231-0620","authenticated-orcid":false,"given":"Maria N.","family":"de Menezes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma V.","family":"Petley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joelle S.","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dat","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick S. K.","family":"Leung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6550-0637","authenticated-orcid":false,"given":"Joan","family":"So","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0759-4035","authenticated-orcid":false,"given":"Christian","family":"Deguit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4416-7040","authenticated-orcid":false,"given":"Joe","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6245-5954","authenticated-orcid":false,"given":"Imran G.","family":"House","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8742-8138","authenticated-orcid":false,"given":"Lev M.","family":"Kats","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M.","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3059-5730","authenticated-orcid":false,"given":"Benjamin J.","family":"Solomon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4555-6582","authenticated-orcid":false,"given":"Simon J.","family":"Harrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2097-6428","authenticated-orcid":false,"given":"Jane","family":"Oliaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3528-478X","authenticated-orcid":false,"given":"Ian A.","family":"Parish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0417-3625","authenticated-orcid":false,"given":"Kylie M.","family":"Quinn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2729-5887","authenticated-orcid":false,"given":"Paul J.","family":"Neeson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clare Y.","family":"Slaney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5884-2786","authenticated-orcid":false,"given":"Junyun","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2116-013X","authenticated-orcid":false,"given":"Paul A.","family":"Beavis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5303-9561","authenticated-orcid":false,"given":"Phillip K.","family":"Darcy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,10]]},"reference":[{"key":"7242_CR1","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1056\/NEJMoa1407222","volume":"371","author":"SL Maude","year":"2014","unstructured":"Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507\u20131517 (2014).","journal-title":"N. Engl. J. Med."},{"key":"7242_CR2","doi-asserted-by":"publisher","first-page":"95ra73","DOI":"10.1126\/scitranslmed.3002842","volume":"3","author":"M Kalos","year":"2011","unstructured":"Kalos, M. et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3, 95ra73 (2011).","journal-title":"Sci. Transl. Med."},{"key":"7242_CR3","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1056\/NEJMoa2213614","volume":"388","author":"P Rodriguez-Otero","year":"2023","unstructured":"Rodriguez-Otero, P. et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N. Engl. J. Med. 388, 1002\u20131014 (2023).","journal-title":"N. Engl. J. Med."},{"key":"7242_CR4","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1056\/NEJMoa2303379","volume":"389","author":"J San-Miguel","year":"2023","unstructured":"San-Miguel, J. et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N. Engl. J. Med. 389, 335\u2013347 (2023).","journal-title":"N. Engl. J. Med."},{"key":"7242_CR5","doi-asserted-by":"publisher","first-page":"eaaw2293","DOI":"10.1126\/scitranslmed.aaw2293","volume":"11","author":"S Mardiana","year":"2019","unstructured":"Mardiana, S., Solomon, B. J., Darcy, P. K. & Beavis, P. A. Supercharging adoptive T cell therapy to overcome solid tumor-induced immunosuppression. Sci. Transl. Med. 11, eaaw2293 (2019).","journal-title":"Sci. Transl. Med."},{"key":"7242_CR6","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1038\/s41577-021-00539-6","volume":"21","author":"JD Chan","year":"2021","unstructured":"Chan, J. D. et al. Cellular networks controlling T cell persistence in adoptive cell therapy. Nat. Rev. Immunol. 21, 769\u2013784 (2021).","journal-title":"Nat. Rev. Immunol."},{"key":"7242_CR7","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1182\/blood.2018885863","volume":"134","author":"JAC van Bruggen","year":"2019","unstructured":"van Bruggen, J. A. C. et al. Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8+ T cells and impede CAR T-cell efficacy. Blood 134, 44\u201358 (2019).","journal-title":"Blood"},{"key":"7242_CR8","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1038\/s41591-018-0010-1","volume":"24","author":"JA Fraietta","year":"2018","unstructured":"Fraietta, J. A. et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat. Med. 24, 563\u2013571 (2018).","journal-title":"Nat. Med."},{"key":"7242_CR9","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1038\/s41577-019-0221-9","volume":"19","author":"CU Blank","year":"2019","unstructured":"Blank, C. U. et al. Defining T cell exhaustion. Nat. Rev. Immunol. 19, 665\u2013674 (2019).","journal-title":"Nat. Rev. Immunol."},{"key":"7242_CR10","doi-asserted-by":"publisher","first-page":"4416","DOI":"10.1158\/1078-0432.CCR-16-2848","volume":"23","author":"NA Giraldo","year":"2017","unstructured":"Giraldo, N. A. et al. Tumor-infiltrating and peripheral blood T-cell immunophenotypes predict early relapse in localized clear cell renal cell carcinoma. Clin. Cancer Res. 23, 4416\u20134428 (2017).","journal-title":"Clin. Cancer Res."},{"key":"7242_CR11","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1016\/j.cell.2018.10.038","volume":"175","author":"M Sade-Feldman","year":"2019","unstructured":"Sade-Feldman, M. et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175, 998\u20131013.e20 (2019).","journal-title":"Cell"},{"key":"7242_CR12","doi-asserted-by":"publisher","first-page":"2379","DOI":"10.1016\/j.ymthe.2020.07.018","volume":"28","author":"L Giuffrida","year":"2020","unstructured":"Giuffrida, L. et al. IL-15 preconditioning augments CAR T cell responses to checkpoint blockade for improved treatment of solid tumors. Mol. Ther. 28, 2379\u20132393 (2020).","journal-title":"Mol. Ther."},{"key":"7242_CR13","doi-asserted-by":"publisher","first-page":"9571","DOI":"10.1073\/pnas.0503726102","volume":"102","author":"CA Klebanoff","year":"2005","unstructured":"Klebanoff, C. A. et al. Central memory self\/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc. Natl Acad. Sci. USA 102, 9571\u20139576 (2005).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"7242_CR14","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.immuni.2018.12.021","volume":"50","author":"I Siddiqui","year":"2019","unstructured":"Siddiqui, I. et al. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50, 195\u2013211.e110 (2019).","journal-title":"Immunity"},{"key":"7242_CR15","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.1158\/1078-0432.CCR-17-0432","volume":"24","author":"Y Guo","year":"2018","unstructured":"Guo, Y. et al. Phase I study of chimeric antigen receptor-modified T cells in patients with EGFR-positive advanced biliary tract cancers. Clin. Cancer Res. 24, 1277\u20131286 (2018).","journal-title":"Clin. Cancer Res."},{"key":"7242_CR16","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.it.2023.01.002","volume":"44","author":"L Soriano-Baguet","year":"2023","unstructured":"Soriano-Baguet, L. & Brenner, D. Metabolism and epigenetics at the heart of T cell function. Trends Immunol. 44, 231\u2013244 (2023).","journal-title":"Trends Immunol."},{"key":"7242_CR17","doi-asserted-by":"publisher","first-page":"eaba1786","DOI":"10.1126\/science.aba1786","volume":"372","author":"EW Weber","year":"2021","unstructured":"Weber, E. W. et al. Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling. Science 372, eaba1786 (2021).","journal-title":"Science"},{"key":"7242_CR18","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1038\/s43018-021-00244-2","volume":"2","author":"K Hirabayashi","year":"2021","unstructured":"Hirabayashi, K. et al. Dual-targeting CAR-T cells with optimal co-stimulation and metabolic fitness enhance antitumor activity and prevent escape in solid tumors. Nat. Cancer 2, 904\u2013918 (2021).","journal-title":"Nat. Cancer"},{"key":"7242_CR19","doi-asserted-by":"publisher","first-page":"E7788","DOI":"10.1073\/pnas.1610544113","volume":"113","author":"LV Hurton","year":"2016","unstructured":"Hurton, L. V. et al. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Proc. Natl Acad. Sci. USA 113, E7788\u2013E7797 (2016).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"7242_CR20","doi-asserted-by":"publisher","first-page":"3479","DOI":"10.1172\/JCI86437","volume":"126","author":"Y Kagoya","year":"2016","unstructured":"Kagoya, Y. et al. BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models. J. Clin. Invest. 126, 3479\u20133494 (2016).","journal-title":"J. Clin. Invest."},{"key":"7242_CR21","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1038\/s41590-021-00964-8","volume":"22","author":"H Seo","year":"2021","unstructured":"Seo, H. et al. BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells. Nat. Immunol. 22, 983\u2013995 (2021).","journal-title":"Nat. Immunol."},{"key":"7242_CR22","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/s41586-019-1805-z","volume":"576","author":"RC Lynn","year":"2019","unstructured":"Lynn, R. C. et al. c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature 576, 293\u2013300 (2019).","journal-title":"Nature"},{"key":"7242_CR23","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1158\/2326-6066.CIR-18-0466","volume":"7","author":"D Alizadeh","year":"2019","unstructured":"Alizadeh, D. et al. IL15 enhances CAR-T cell antitumor activity by reducing mTORC1 activity and preserving their stem cell memory phenotype. Cancer Immunol. Res. 7, 759\u2013772 (2019).","journal-title":"Cancer Immunol. Res."},{"key":"7242_CR24","doi-asserted-by":"publisher","first-page":"187","DOI":"10.4049\/jimmunol.1300331","volume":"191","author":"MM Tejera","year":"2013","unstructured":"Tejera, M. M., Kim, E. H., Sullivan, J. A., Plisch, E. H. & Suresh, M. FoxO1 controls effector-to-memory transition and maintenance of functional CD8 T cell memory. J. Immunol. 191, 187\u2013199 (2013).","journal-title":"J. Immunol."},{"key":"7242_CR25","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1038\/ni.1689","volume":"10","author":"YM Kerdiles","year":"2009","unstructured":"Kerdiles, Y. M. et al. Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat. Immunol. 10, 176\u2013184 (2009).","journal-title":"Nat. Immunol."},{"key":"7242_CR26","doi-asserted-by":"publisher","first-page":"1262","DOI":"10.1016\/j.cell.2021.02.019","volume":"184","author":"Z Chen","year":"2021","unstructured":"Chen, Z. et al. In vivo CD8+ T cell CRISPR screening reveals control by Fli1 in infection and cancer. Cell 184, 1262\u20131280.e1222 (2021).","journal-title":"Cell"},{"key":"7242_CR27","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1038\/ni.2158","volume":"12","author":"CY Yang","year":"2011","unstructured":"Yang, C. Y. et al. The transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsets. Nat. Immunol. 12, 1221\u20131229 (2011).","journal-title":"Nat. Immunol."},{"key":"7242_CR28","doi-asserted-by":"publisher","first-page":"3454","DOI":"10.1016\/j.celrep.2018.03.020","volume":"22","author":"DT Utzschneider","year":"2018","unstructured":"Utzschneider, D. T. et al. Active maintenance of T cell memory in acute and chronic viral infection depends on continuous expression of FOXO1. Cell Rep. 22, 3454\u20133467 (2018).","journal-title":"Cell Rep."},{"key":"7242_CR29","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.redox.2015.06.019","volume":"6","author":"LO Klotz","year":"2015","unstructured":"Klotz, L. O. et al. Redox regulation of FoxO transcription factors. Redox Biol. 6, 51\u201372 (2015).","journal-title":"Redox Biol."},{"key":"7242_CR30","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1172\/JCI89455","volume":"127","author":"PA Beavis","year":"2017","unstructured":"Beavis, P. A. et al. Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy. J. Clin. Invest. 127, 929\u2013941 (2017).","journal-title":"J. Clin. Invest."},{"key":"7242_CR31","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1038\/s41392-020-00357-7","volume":"6","author":"E Dong","year":"2021","unstructured":"Dong, E. et al. IFN-\u03b3 surmounts PD-L1\/PD1 inhibition to CAR-T cell therapy by upregulating ICAM-1 on tumor cells. Signal Transduct. Target. Ther. 6, 20 (2021).","journal-title":"Signal Transduct. Target. Ther."},{"key":"7242_CR32","doi-asserted-by":"publisher","first-page":"5697","DOI":"10.1158\/0008-5472.CAN-11-0103","volume":"71","author":"M Chmielewski","year":"2011","unstructured":"Chmielewski, M., Kopecky, C., Hombach, A. A. & Abken, H. IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression. Cancer Res. 71, 5697\u20135706 (2011).","journal-title":"Cancer Res."},{"key":"7242_CR33","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1038\/s41586-022-04585-5","volume":"604","author":"RC Larson","year":"2022","unstructured":"Larson, R. C. et al. CAR T cell killing requires the IFN\u03b3R pathway in solid but not liquid tumours. Nature 604, 563\u2013570 (2022).","journal-title":"Nature"},{"key":"7242_CR34","doi-asserted-by":"publisher","first-page":"1296","DOI":"10.1158\/0008-5472.CAN-16-1831","volume":"77","author":"S Mardiana","year":"2017","unstructured":"Mardiana, S. et al. A multifunctional role for adjuvant anti-4-1BB therapy in augmenting antitumor response by chimeric antigen receptor T cells. Cancer Res. 77, 1296\u20131309 (2017).","journal-title":"Cancer Res."},{"key":"7242_CR35","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.1158\/2326-6066.CIR-20-0837","volume":"9","author":"C Kantari-Mimoun","year":"2021","unstructured":"Kantari-Mimoun, C. et al. CAR T-cell entry into tumor islets is a two-step process dependent on IFN\u03b3 and ICAM-1. Cancer Immunol. Res. 9, 1425\u20131438 (2021).","journal-title":"Cancer Immunol. Res."},{"key":"7242_CR36","doi-asserted-by":"publisher","first-page":"100938","DOI":"10.1016\/j.mex.2020.100938","volume":"7","author":"LB Monteiro","year":"2020","unstructured":"Monteiro, L. B., Davanzo, G. G., de Aguiar, C. F. & Moraes-Vieira, P. M. M. Using flow cytometry for mitochondrial assays. MethodsX 7, 100938 (2020).","journal-title":"MethodsX"},{"key":"7242_CR37","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7750","volume":"6","author":"KJ Jang","year":"2015","unstructured":"Jang, K. J. et al. Mitochondrial function provides instructive signals for activation-induced B-cell fates. Nat. Commun. 6, 6750 (2015).","journal-title":"Nat. Commun."},{"key":"7242_CR38","doi-asserted-by":"publisher","first-page":"e0232915","DOI":"10.1371\/journal.pone.0232915","volume":"15","author":"SMA Rad","year":"2020","unstructured":"Rad, S. M. A., Poudel, A., Tan, G. M. Y. & McLellan, A. D. Promoter choice: Who should drive the CAR in T cells? PLoS ONE 15, e0232915 (2020).","journal-title":"PLoS ONE"},{"key":"7242_CR39","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1016\/j.immuni.2007.09.006","volume":"27","author":"EJ Wherry","year":"2007","unstructured":"Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670\u2013684 (2007).","journal-title":"Immunity"},{"key":"7242_CR40","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1038\/s41590-022-01263-6","volume":"23","author":"Q Shan","year":"2022","unstructured":"Shan, Q. et al. Tcf1\u2013CTCF cooperativity shapes genomic architecture to promote CD8+ T cell homeostasis. Nat. Immunol. 23, 1222\u20131235 (2022).","journal-title":"Nat. Immunol."},{"key":"7242_CR41","doi-asserted-by":"publisher","first-page":"108674","DOI":"10.1016\/j.celrep.2020.108674","volume":"34","author":"A Delpoux","year":"2021","unstructured":"Delpoux, A. et al. FOXO1 constrains activation and regulates senescence in CD8 T cells. Cell Rep. 34, 108674 (2021).","journal-title":"Cell Rep."},{"key":"7242_CR42","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1038\/s41586-021-04390-6","volume":"602","author":"JJ Melenhorst","year":"2022","unstructured":"Melenhorst, J. J. et al. Decade-long leukaemia remissions with persistence of CD4+ CAR T cells. Nature 602, 503\u2013509 (2022).","journal-title":"Nature"},{"key":"7242_CR43","doi-asserted-by":"publisher","first-page":"e95103","DOI":"10.1172\/jci.insight.95103","volume":"2","author":"CA Klebanoff","year":"2017","unstructured":"Klebanoff, C. A. et al. Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy. JCI Insight 2, e95103 (2017).","journal-title":"JCI Insight"},{"key":"7242_CR44","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/j.bone.2011.06.034","volume":"50","author":"S Kousteni","year":"2012","unstructured":"Kousteni, S. FoxO1, the transcriptional chief of staff of energy metabolism. Bone 50, 437\u2013443 (2012).","journal-title":"Bone"},{"key":"7242_CR45","doi-asserted-by":"publisher","first-page":"4049","DOI":"10.1016\/j.cell.2022.09.020","volume":"185","author":"Q Huang","year":"2022","unstructured":"Huang, Q. et al. The primordial differentiation of tumor-specific memory CD8+ T cells as bona fide responders to PD-1\/PD-L1 blockade in draining lymph nodes. Cell 185, 4049\u20134066.e4025 (2022).","journal-title":"Cell"},{"key":"7242_CR46","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1126\/science.aay5967","volume":"367","author":"K Reinhard","year":"2020","unstructured":"Reinhard, K. et al. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. Science 367, 446\u2013453 (2020).","journal-title":"Science"},{"key":"7242_CR47","doi-asserted-by":"publisher","first-page":"5787","DOI":"10.4049\/jimmunol.171.11.5787","volume":"171","author":"MP Piechocki","year":"2003","unstructured":"Piechocki, M. P., Ho, Y. S., Pilon, S. & Wei, W. Z. Human ErbB-2 (Her-2) transgenic mice: a model system for testing Her-2 based vaccines. J. Immunol. 171, 5787\u20135794 (2003).","journal-title":"J. Immunol."},{"key":"7242_CR48","doi-asserted-by":"publisher","first-page":"3705","DOI":"10.4049\/jimmunol.164.7.3705","volume":"164","author":"PK Darcy","year":"2000","unstructured":"Darcy, P. K. et al. Redirected perforin-dependent lysis of colon carcinoma by ex vivo genetically engineered CTL. J. Immunol. 164, 3705\u20133712 (2000).","journal-title":"J. Immunol."},{"key":"7242_CR49","doi-asserted-by":"publisher","first-page":"1530","DOI":"10.1093\/bioinformatics\/bts196","volume":"28","author":"DS DeLuca","year":"2012","unstructured":"DeLuca, D. S. et al. RNA-SeQC: RNA-seq metrics for quality control and process optimization. Bioinformatics 28, 1530\u20131532 (2012).","journal-title":"Bioinformatics"},{"key":"7242_CR50","doi-asserted-by":"publisher","first-page":"D754","DOI":"10.1093\/nar\/gkx1098","volume":"46","author":"DR Zerbino","year":"2018","unstructured":"Zerbino, D. R. et al. Ensembl 2018. Nucleic Acids Res. 46, D754\u2013D761 (2018).","journal-title":"Nucleic Acids Res."},{"key":"7242_CR51","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","volume":"26","author":"MD Robinson","year":"2010","unstructured":"Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139\u2013140 (2010).","journal-title":"Bioinformatics"},{"key":"7242_CR52","doi-asserted-by":"publisher","first-page":"4288","DOI":"10.1093\/nar\/gks042","volume":"40","author":"DJ McCarthy","year":"2012","unstructured":"McCarthy, D. J., Chen, Y. & Smyth, G. K. Differential expression analysis of multifactor RNA-seq experiments with respect to biological variation. Nucleic Acids Res. 40, 4288\u20134297 (2012).","journal-title":"Nucleic Acids Res."},{"key":"7242_CR53","doi-asserted-by":"publisher","unstructured":"Korotkevich, G., Sukhov, V. & Sergushichev, A. Fast gene set enrichment analysis. Preprint at bioRxiv https:\/\/doi.org\/10.1101\/060012 (2019).","DOI":"10.1101\/060012"},{"key":"7242_CR54","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545\u201315550 (2005).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"7242_CR55","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1093\/bioinformatics\/btr260","volume":"27","author":"A Liberzon","year":"2011","unstructured":"Liberzon, A. et al. Molecular signatures database (MSigDB) 3.0. Bioinformatics 27, 1739\u20131740 (2011).","journal-title":"Bioinformatics"},{"key":"7242_CR56","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","volume":"1","author":"A Liberzon","year":"2015","unstructured":"Liberzon, A. et al. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 1, 417\u2013425 (2015).","journal-title":"Cell Syst."},{"key":"7242_CR57","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/nar\/28.1.27","volume":"28","author":"M Kanehisa","year":"2000","unstructured":"Kanehisa, M. & Goto, S. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res. 28, 27\u201330 (2000).","journal-title":"Nucleic Acids Res."},{"key":"7242_CR58","doi-asserted-by":"publisher","first-page":"e133","DOI":"10.1093\/nar\/gkz601","volume":"47","author":"F Pont","year":"2019","unstructured":"Pont, F., Tosolini, M. & Fournie, J. J. Single-cell signature explorer for comprehensive visualization of single cell signatures across scRNA-seq datasets. Nucleic Acids Res. 47, e133 (2019).","journal-title":"Nucleic Acids Res."},{"key":"7242_CR59","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1186\/s12859-018-2579-2","volume":"19","author":"JM Gaspar","year":"2018","unstructured":"Gaspar, J. M. NGmerge: merging paired-end reads via novel empirically-derived models of sequencing errors. BMC Bioinformatics 19, 536 (2018).","journal-title":"BMC Bioinformatics"},{"key":"7242_CR60","doi-asserted-by":"publisher","first-page":"1618","DOI":"10.1093\/bioinformatics\/btu056","volume":"30","author":"A Pohl","year":"2014","unstructured":"Pohl, A. & Beato, M. bwtool: a tool for bigWig files. Bioinformatics 30, 1618\u20131619 (2014).","journal-title":"Bioinformatics"},{"key":"7242_CR61","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1038\/nmeth.4401","volume":"14","author":"AN Schep","year":"2017","unstructured":"Schep, A. N., Wu, B., Buenrostro, J. D. & Greenleaf, W. J. chromVAR: inferring transcription-factor-associated accessibility from single-cell epigenomic data. Nat. Methods 14, 975\u2013978 (2017).","journal-title":"Nat. Methods"},{"key":"7242_CR62","doi-asserted-by":"publisher","first-page":"D165","DOI":"10.1093\/nar\/gkab1113","volume":"50","author":"JA Castro-Mondragon","year":"2022","unstructured":"Castro-Mondragon, J. A. et al. JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 50, D165\u2013D173 (2022).","journal-title":"Nucleic Acids Res."}],"container-title":["Nature"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41586-024-07242-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-024-07242-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-024-07242-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T09:02:31Z","timestamp":1715072551000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41586-024-07242-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,10]]},"references-count":62,"journal-issue":{"issue":"8010","published-print":{"date-parts":[[2024,5,2]]}},"alternative-id":["7242"],"URL":"https:\/\/doi.org\/10.1038\/s41586-024-07242-1","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-2584153\/v1","asserted-by":"object"}]},"ISSN":["0028-0836","1476-4687"],"issn-type":[{"value":"0028-0836","type":"print"},{"value":"1476-4687","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,10]]},"assertion":[{"value":"13 February 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 February 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 April 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"P.A.B. declares research funding from AstraZeneca, Bristol-Myers-Squibb and Gilead Sciences. P.K.D. declares research funding from Myeloid Therapeutics, Prescient Therapeutics, Bristol-Myers-Squibb and Juno Therapeutics. J. Lai is a present employee at oNKo-Innate.\u00a0S.J.H. declares\u00a0consultancy fees and honoraria\u00a0from Celgene, Janssen Cilag and Novartis; declares\u00a0research funding from\u00a0Celgene, Janssen Cilag,\u00a0Novartis and Haemalogix; was an\u00a0investigator on studies for\u00a0Celgene, Janssen Cilag,\u00a0Novartis and Haemalogix; and has served on the advisory board for\u00a0Celgene, Janssen Cilag,\u00a0Novartis and Haemalogix. I.A.P. declares research funding from Bristol-Myers-Squibb and Astrazeneca. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}