{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:23:10Z","timestamp":1785424990217,"version":"3.56.0"},"reference-count":61,"publisher":"Rockefeller University Press","issue":"8","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006390","name":"University of Lausanne","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006390","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008401","name":"Max Clo\u00ebtta Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008401","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["310030_182680"],"award-info":[{"award-number":["310030_182680"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["310030_200898"],"award-info":[{"award-number":["310030_200898"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017035","name":"ISREC Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100017035","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013362","name":"Swiss Cancer Research Foundation","doi-asserted-by":"publisher","award":["KFS-5770-02-2023"],"award-info":[{"award-number":["KFS-5770-02-2023"]}],"id":[{"id":"10.13039\/501100013362","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013362","name":"Swiss Cancer Research Foundation","doi-asserted-by":"publisher","award":["KFS-5386-08-2021"],"award-info":[{"award-number":["KFS-5386-08-2021"]}],"id":[{"id":"10.13039\/501100013362","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,8,3]]},"abstract":"<jats:p>T cell exhaustion is a major obstacle to effective immunotherapy in cancer and chronic infection. Here, we identify the transcription factor IRF8 as a tumor-specific regulator of CD8+ T cell exhaustion. IRF8 is strongly expressed in tumor-reactive CD8+ T cells but not during chronic viral infection. Its expression is induced by TCR signaling and can be suppressed by type I IFN (IFN-I). Sustained IFN-I signaling, a hallmark of chronic infection, correlates with reduced chromatin accessibility at the Irf8 locus and progressive repression of Irf8 expression. In tumor-specific CD8+ T cells, IRF8 overexpression enhanced TOX expression while reducing IFN\u03b3, granzyme B, and TNF production. Conversely, Irf8 deficiency diminished exhaustion, restored effector functions, and improved tumor control. Mechanistically, IRF8 directly binds the Tox locus and promotes its transcription. We further show that additional IRF-family transcription factors contribute similarly to the exhausted T cell program, identifying this transcriptional network as a key regulator of tumor-associated T cell dysfunction.<\/jats:p>","DOI":"10.1084\/jem.20252115","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T06:21:03Z","timestamp":1780122063000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["The transcription factor IRF8 drives tumor-specific exhaustion in CD8+ T cells"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2474-8607","authenticated-orcid":true,"given":"Marco","family":"Ongaro","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Institute for Cancer Research, University of Lausanne 2 , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4602-5388","authenticated-orcid":true,"given":"Romane","family":"Thouenon","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Institute for Cancer Research, University of Lausanne 2 , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3151-3901","authenticated-orcid":true,"given":"Isaac","family":"Crespo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Institute for Cancer Research, University of Lausanne 2 , Lausanne,","place":["Switzerland"]},{"name":"SIB Swiss Institute of Bioinformatics 3 , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7123-4336","authenticated-orcid":true,"given":"Alexandre","family":"Dumez","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2028-1327","authenticated-orcid":true,"given":"M\u00e9lanie","family":"Charmoy","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1937-5009","authenticated-orcid":true,"given":"Eduardo","family":"Roman Camacho","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Institute for Cancer Research, University of Lausanne 2 , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8823-3823","authenticated-orcid":true,"given":"Victoria J.","family":"Morel","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Institute for Cancer Research, University of Lausanne 2 , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6125-9775","authenticated-orcid":true,"given":"Daniela","family":"Cropp","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Institute for Cancer Research, University of Lausanne 2 , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0098-9190","authenticated-orcid":true,"given":"Emma","family":"Desponds","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Institute for Cancer Research, University of Lausanne 2 , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9116-0262","authenticated-orcid":true,"given":"Giulio","family":"Zanette","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Institute for Cancer Research, University of Lausanne 2 , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3818-6138","authenticated-orcid":true,"given":"Yi-Chuan","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Institute for Cancer Research, University of Lausanne 2 , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0507-9611","authenticated-orcid":true,"given":"Letizia","family":"Vergili","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Institute for Cancer Research, University of Lausanne 2 , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8163-0837","authenticated-orcid":true,"given":"Laure","family":"Till\u00e9","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Institute for Cancer Research, University of Lausanne 2 , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7649-7573","authenticated-orcid":true,"given":"In\u00e9s","family":"Di Resta","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Institute for Cancer Research, University of Lausanne 2 , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6919-2855","authenticated-orcid":true,"given":"Marine M.","family":"Leblond","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Institute for Cancer Research, University of Lausanne 2 , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6844-6170","authenticated-orcid":true,"given":"J\u00e9sus","family":"Corria Osorio","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Institute for Cancer Research, University of Lausanne 2 , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3078-3774","authenticated-orcid":true,"given":"Ping-Chih","family":"Ho","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Institute for Cancer Research, University of Lausanne 2 , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3292-1536","authenticated-orcid":true,"given":"Werner","family":"Held","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9445-8474","authenticated-orcid":true,"given":"Gr\u00e9gory","family":"Verdeil","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Lausanne 1 Department of Fundamental Oncology UNIL, , Lausanne,","place":["Switzerland"]},{"id":[{"id":"https:\/\/ror.org\/019whta54","id-type":"ROR","asserted-by":"publisher"}],"name":"Ludwig Institute for Cancer Research, University of Lausanne 2 , Lausanne,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"2026062209514659900_bib1","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1038\/nmeth.4463","article-title":"SCENIC: Single-cell regulatory network inference and clustering","volume":"14","author":"Aibar","year":"2017","journal-title":"Nat. Methods"},{"key":"2026062209514659900_bib2","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/s41586-019-1326-9","article-title":"TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection","volume":"571","author":"Alfei","year":"2019","journal-title":"Nature"},{"key":"2026062209514659900_bib3","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1182\/blood-2002-04-1088","article-title":"Essential role for ICSBP in the in vivo development of murine CD8alpha + dendritic cells","volume":"101","author":"Aliberti","year":"2003","journal-title":"Blood"},{"key":"2026062209514659900_bib4","doi-asserted-by":"publisher","first-page":"2965","DOI":"10.1038\/s41467-021-23324-4","article-title":"Interpretation of T cell states from single-cell transcriptomics data using reference atlases","volume":"12","author":"Andreatta","year":"2021","journal-title":"Nat. Commun."},{"key":"2026062209514659900_bib5","doi-asserted-by":"publisher","first-page":"D1109","DOI":"10.1093\/nar\/gkab1055","article-title":"SPICA: Swiss portal for immune cell analysis","volume":"50","author":"Andreatta","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"2026062209514659900_bib6","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.3389\/fimmu.2019.01176","article-title":"Direct inhibition of IRF-dependent transcriptional regulatory mechanisms associated with disease","volume":"10","author":"Antonczyk","year":"2019","journal-title":"Front. Immunol."},{"key":"2026062209514659900_bib7","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1038\/s41586-024-07762-w","article-title":"Single-cell CAR T atlas reveals type 2 function in 8-year leukaemia remission","volume":"634","author":"Bai","year":"2024","journal-title":"Nature"},{"key":"2026062209514659900_bib8","doi-asserted-by":"publisher","first-page":"2699","DOI":"10.1016\/j.immuni.2023.11.005","article-title":"Stat5 opposes the transcription factor Tox and rewires exhausted CD8+ T cells toward durable effector-like states during chronic antigen exposure","volume":"56","author":"Beltra","year":"2023","journal-title":"Immunity"},{"key":"2026062209514659900_bib9","doi-asserted-by":"publisher","first-page":"2169","DOI":"10.1084\/jem.20140425","article-title":"The transcription factors IRF8 and PU.1 negatively regulate plasma cell differentiation","volume":"211","author":"Carotta","year":"2014","journal-title":"J. Exp. Med."},{"key":"2026062209514659900_bib10","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1038\/s41586-019-0985-x","article-title":"NR4A transcription factors limit CAR T cell function in solid tumours","volume":"567","author":"Chen","year":"2019","journal-title":"Nature"},{"key":"2026062209514659900_bib11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41423-025-01378-4","article-title":"Regulation of T cell exhaustion and stemness: Molecular mechanisms and implications for cancer immunotherapy","volume":"23","author":"Chen","year":"2026","journal-title":"Cell Mol. Immunol."},{"key":"2026062209514659900_bib12","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1016\/j.immuni.2012.08.021","article-title":"Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory","volume":"37","author":"Doering","year":"2012","journal-title":"Immunity"},{"key":"2026062209514659900_bib13","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1038\/s41591-018-0010-1","article-title":"Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia","volume":"24","author":"Fraietta","year":"2018","journal-title":"Nat. Med."},{"key":"2026062209514659900_bib14","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adf7579","article-title":"Regulatory circuits of mitophagy restrict distinct modes of cell death during memory CD8+ T cell formation","volume":"8","author":"Franco","year":"2023","journal-title":"Sci. Immunol."},{"key":"2026062209514659900_bib15","doi-asserted-by":"publisher","first-page":"1600","DOI":"10.1038\/s41590-022-01338-4","article-title":"Shared and distinct biological circuits in effector, memory and exhausted CD8+ T cells revealed by temporal single-cell transcriptomics and epigenetics","volume":"23","author":"Giles","year":"2022","journal-title":"Nat. Immunol."},{"key":"2026062209514659900_bib16","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1038\/ni.3197","article-title":"Batf3 maintains autoactivation of Irf8 for commitment of a CD8\u03b1(+) conventional DC clonogenic progenitor","volume":"16","author":"Grajales-Reyes","year":"2015","journal-title":"Nat. Immunol."},{"key":"2026062209514659900_bib17","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks543","article-title":"i-cisTarget: an integrative genomics method for the prediction of regulatory features and cis-regulatory modules","volume":"40","author":"Herrmann","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2026062209514659900_bib18","doi-asserted-by":"publisher","first-page":"2085","DOI":"10.1038\/s41467-017-01070-w","article-title":"IRF8-dependent molecular complexes control the Th9 transcriptional program","volume":"8","author":"Humblin","year":"2017","journal-title":"Nat. Commun."},{"key":"2026062209514659900_bib19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0012776","article-title":"Inferring regulatory networks from expression data using tree-based methods","volume":"5","author":"Huynh-Thu","year":"2010","journal-title":"PLoS One"},{"key":"2026062209514659900_bib20","doi-asserted-by":"crossref","first-page":"W57","DOI":"10.1093\/nar\/gkv395","article-title":"i-cisTarget 2015 update: generalized cis-regulatory enrichment analysis in human, mouse and fly","volume":"43","author":"Imrichov\u00e1","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"2026062209514659900_bib21","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1038\/s41586-019-1836-5","article-title":"An intra-tumoral niche maintains and differentiates stem-like CD8 T cells","volume":"576","author":"Jansen","year":"2019","journal-title":"Nature"},{"key":"2026062209514659900_bib22","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20220679","article-title":"Clonal lineage tracing reveals mechanisms skewing CD8+ T cell fate decisions in chronic infection","volume":"220","author":"Kasmani","year":"2023","journal-title":"J. Exp. Med."},{"key":"2026062209514659900_bib23","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1101\/gr.229102","article-title":"The human genome browser at UCSC","volume":"12","author":"Kent","year":"2002","journal-title":"Genome Res."},{"key":"2026062209514659900_bib24","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1038\/s41586-019-1325-x","article-title":"TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion","volume":"571","author":"Khan","year":"2019","journal-title":"Nature"},{"key":"2026062209514659900_bib25","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1038\/s41586-025-09489-8","article-title":"In vivo CRISPR screens identify modifiers of CAR T cell function in myeloma","volume":"646","author":"Knudsen","year":"2025","journal-title":"Nature"},{"key":"2026062209514659900_bib26","doi-asserted-by":"publisher","first-page":"4978","DOI":"10.1038\/ncomms5978","article-title":"IRF8 inhibits C\/EBPalpha activity to restrain mononuclear phagocyte progenitors from differentiating into neutrophils","volume":"5","author":"Kurotaki","year":"2014","journal-title":"Nat. Commun."},{"key":"2026062209514659900_bib27","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.1158\/2326-6066.cir-19-0826","article-title":"CD40 Agonist restores the antitumor efficacy of anti-PD1 therapy in muscle-invasive bladder cancer in an IFN I\/II-mediated manner","volume":"8","author":"Leblond","year":"2020","journal-title":"Cancer Immunol. Res."},{"key":"2026062209514659900_bib28","doi-asserted-by":"publisher","first-page":"2280","DOI":"10.1038\/s41590-025-02330-4","article-title":"Analysis of the three-dimensional genome of exhausted CD8+ T cells reveals a critical role of IRF8 in their differentiation and functions in cancer","volume":"26","author":"Li","year":"2025","journal-title":"Nat. Immunol."},{"key":"2026062209514659900_bib29","doi-asserted-by":"publisher","first-page":"2369","DOI":"10.1016\/j.immuni.2022.10.020","article-title":"The transcription factor IRF2 drives interferon-mediated CD8(+) T cell exhaustion to restrict anti-tumor immunity","volume":"55","author":"Lukhele","year":"2022","journal-title":"Immunity"},{"key":"2026062209514659900_bib30","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1038\/s41423-026-01405-y","article-title":"T cell adaptation in chronic infections and tumors","volume":"23","author":"Luxenburger","year":"2026","journal-title":"Cell Mol. Immunol."},{"key":"2026062209514659900_bib31","doi-asserted-by":"publisher","DOI":"10.1126\/science.adj3020","article-title":"Nutrient-driven histone code determines exhausted CD8+ T cell fates","volume":"387","author":"Ma","year":"2025","journal-title":"Science"},{"key":"2026062209514659900_bib32","doi-asserted-by":"publisher","first-page":"4280","DOI":"10.1038\/s44318-025-00485-2","article-title":"Transcription factor IRF-5 regulates lipid metabolism and mitochondrial function in murine CD8+ T-cells during viral infection","volume":"44","author":"Mai","year":"2025","journal-title":"EMBO J."},{"key":"2026062209514659900_bib33","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1016\/j.immuni.2017.11.021","article-title":"Transcription factor IRF4 promotes CD8+ T cell exhaustion and limits the development of memory-like T cells during chronic infection","volume":"47","author":"Man","year":"2017","journal-title":"Immunity"},{"key":"2026062209514659900_bib34","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1038\/ni.2710","article-title":"The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells","volume":"14","author":"Man","year":"2013","journal-title":"Nat. Immunol."},{"key":"2026062209514659900_bib35","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.immuni.2015.01.006","article-title":"The transcription factor NFAT promotes exhaustion of activated CD8+ T cells","volume":"42","author":"Martinez","year":"2015","journal-title":"Immunity"},{"key":"2026062209514659900_bib36","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1146\/annurev-immunol-041015-055318","article-title":"CD8 T cell exhaustion during chronic viral infection and cancer","volume":"37","author":"McLane","year":"2019","journal-title":"Annu. Rev. Immunol."},{"key":"2026062209514659900_bib37","doi-asserted-by":"publisher","first-page":"12123","DOI":"10.1073\/pnas.1201453109","article-title":"Interferon regulatory factor 8 integrates T-cell receptor and cytokine-signaling pathways and drives effector differentiation of CD8 T cells","volume":"109","author":"Miyagawa","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026062209514659900_bib38","doi-asserted-by":"publisher","first-page":"3711","DOI":"10.4049\/jimmunol.156.10.3711","article-title":"Expression of IFN regulatory factor family proteins in lymphocytes. Induction of Stat-1 and IFN consensus sequence binding protein expression by T cell activation","volume":"156","author":"Nelson","year":"1996","journal-title":"J. Immunol."},{"key":"2026062209514659900_bib39","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1038\/ncomms1311","article-title":"Transcription factor IRF8 directs a silencing programme for TH17 cell differentiation","volume":"2","author":"Ouyang","year":"2011","journal-title":"Nat. Commun."},{"key":"2026062209514659900_bib40","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1038\/nature22367","article-title":"Chromatin states define tumour-specific T cell dysfunction and reprogramming","volume":"545","author":"Philip","year":"2017","journal-title":"Nature"},{"key":"2026062209514659900_bib41","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.coi.2019.04.014","article-title":"Heterogeneity and fate choice: T cell exhaustion in cancer and chronic infections","volume":"58","author":"Philip","year":"2019","journal-title":"Curr. Opin. Immunol."},{"key":"2026062209514659900_bib42","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1038\/342559a0","article-title":"Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen","volume":"342","author":"Pircher","year":"1989","journal-title":"Nature"},{"key":"2026062209514659900_bib43","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/s41586-019-1324-y","article-title":"TOX is a critical regulator of tumour-specific T cell differentiation","volume":"571","author":"Scott","year":"2019","journal-title":"Nature"},{"key":"2026062209514659900_bib44","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1038\/s41590-021-00964-8","article-title":"BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells","volume":"22","author":"Seo","year":"2021","journal-title":"Nat. Immunol."},{"key":"2026062209514659900_bib45","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1007\/s11515-014-1318-y","article-title":"IRF4 and IRF8: Governing the virtues of B lymphocytes","volume":"9","author":"Shukla","year":"2014","journal-title":"Front. Biol. (Beijing)"},{"key":"2026062209514659900_bib46","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0155420","article-title":"Interferon regulator factor 8 (IRF8) limits ocular pathology during HSV-1 infection by restraining the activation and expansion of CD8+ T cells","volume":"11","author":"Sun","year":"2016","journal-title":"PLoS One"},{"key":"2026062209514659900_bib47","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1038\/s41577-025-01221-x","article-title":"Regulators of CD8(+) T cell exhaustion","volume":"26","author":"Sun","year":"2026","journal-title":"Nat. Rev. Immunol."},{"key":"2026062209514659900_bib48","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1126\/science.1235214","article-title":"Persistent LCMV infection is controlled by blockade of type I interferon signaling","volume":"340","author":"Teijaro","year":"2013","journal-title":"Science"},{"key":"2026062209514659900_bib49","doi-asserted-by":"publisher","first-page":"3322","DOI":"10.1021\/acs.jproteome.5b00354","article-title":"Analysis of the human adult urinary metabolome variations with age, body mass index, and gender by implementing a comprehensive workflow for univariate and OPLS statistical analyses","volume":"14","author":"Th\u00e9venot","year":"2015","journal-title":"J. Proteome Res."},{"key":"2026062209514659900_bib50","doi-asserted-by":"publisher","first-page":"1645","DOI":"10.1038\/s41590-023-01614-x","article-title":"Activation of the transcription factor NFAT5 in the tumor microenvironment enforces CD8+ T cell exhaustion","volume":"24","author":"Tille","year":"2023","journal-title":"Nat. Immunol."},{"key":"2026062209514659900_bib51","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.immuni.2016.07.021","article-title":"T cell factor 1-expressing memory-like CD8(+) T cells sustain the immune response to chronic viral infections","volume":"45","author":"Utzschneider","year":"2016","journal-title":"Immunity"},{"key":"2026062209514659900_bib52","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1038\/ni.2606","article-title":"T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion","volume":"14","author":"Utzschneider","year":"2013","journal-title":"Nat. Immunol."},{"key":"2026062209514659900_bib53","doi-asserted-by":"publisher","first-page":"E7240","DOI":"10.1073\/pnas.1608555113","article-title":"Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8+ T cells","volume":"113","author":"Wang","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026062209514659900_bib54","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1038\/ni.2035","article-title":"T cell exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat. Immunol."},{"key":"2026062209514659900_bib55","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/nri3862","article-title":"Molecular and cellular insights into T cell exhaustion","volume":"15","author":"Wherry","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"2026062209514659900_bib56","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1126\/science.1235208","article-title":"Blockade of chronic type I interferon signaling to control persistent LCMV infection","volume":"340","author":"Wilson","year":"2013","journal-title":"Science"},{"key":"2026062209514659900_bib57","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1038\/s41392-025-02327-3","article-title":"Revitalizing T cells: Breakthroughs and challenges in overcoming T cell exhaustion","volume":"11","author":"Wu","year":"2026","journal-title":"Signal Transduct. Target. Ther."},{"key":"2026062209514659900_bib58","doi-asserted-by":"publisher","first-page":"108087","DOI":"10.1016\/j.isci.2023.108087","article-title":"The transcription factor IRF4 determines the anti-tumor immunity of CD8+ T cells","volume":"26","author":"Yan","year":"2023","journal-title":"iScience"},{"key":"2026062209514659900_bib59","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1182\/blood-2014-09-600833","article-title":"IRF8 acts in lineage-committed rather than oligopotent progenitors to control neutrophil vs monocyte production","volume":"125","author":"Yanez","year":"2015","journal-title":"Blood"},{"key":"2026062209514659900_bib60","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1016\/j.immuni.2013.10.007","article-title":"Interferon regulatory factor 4 sustains CD8(+) T cell expansion and effector differentiation","volume":"39","author":"Yao","year":"2013","journal-title":"Immunity"},{"key":"2026062209514659900_bib61","doi-asserted-by":"publisher","first-page":"W175","DOI":"10.1093\/nar\/gkac199","article-title":"ChIP-Atlas 2021 update: A data-mining suite for exploring epigenomic landscapes by fully integrating ChIP-seq, ATAC-seq and Bisulfite-seq data","volume":"50","author":"Zou","year":"2022","journal-title":"Nucleic Acids Res."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20252115\/2036829\/jem_20252115.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20252115\/2036829\/jem_20252115.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T13:52:01Z","timestamp":1782136321000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/223\/8\/e20252115\/282754\/The-transcription-factor-IRF8-drives-tumor"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,22]]},"references-count":61,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8,3]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20252115","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,22]]},"article-number":"e20252115"}}