{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T18:31:41Z","timestamp":1775068301371,"version":"3.50.1"},"reference-count":73,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["R01 CA255334"],"award-info":[{"award-number":["R01 CA255334"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["P01 CA278732"],"award-info":[{"award-number":["P01 CA278732"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Immunol"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Progenitor CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u2009cells differentiate into effector and exhausted progenies during chronic antigen stimulation; however, mechanisms that restrain exhaustion and sustain effector differentiation remain incompletely defined. Here we identified the transcription factor ZFP148 as a repressor of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u2009cell effector differentiation. ZFP148-deficient CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u2009cells displayed increased frequency of cytolytic effector cells and reduced frequency of exhausted cells compared with\n                    <jats:italic>Zfp148<\/jats:italic>\n                    <jats:sup>fl\/fl<\/jats:sup>\n                    controls during chronic viral infection. Mechanistically, ZFP148 limited the chromatin accessibility of effector-driving transcription factor motifs and directly repressed expression of the transcription factor KLF2. Furthermore, conditional ZFP148 ablation in CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u2009cells synergized with programmed cell death-1 blockade to improve tumor control in syngeneic mouse models. Consistently, cancer patients with lower\n                    <jats:italic>ZNF148<\/jats:italic>\n                    expression in tumor-infiltrating CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u2009cells showed improved responsiveness to immunotherapies. Collectively, our study identifies ZFP148 as a transcriptional repressor of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u2009cell effector differentiation and highlights its therapeutic potential for enhancing antitumor immunity.\n                  <\/jats:p>","DOI":"10.1038\/s41590-026-02461-2","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T10:02:26Z","timestamp":1774605746000},"page":"827-840","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ZFP148 is a transcriptional repressor of cytolytic effector CD8+ T cell differentiation"],"prefix":"10.1038","volume":"27","author":[{"given":"Tong","family":"Xiao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9284-4950","authenticated-orcid":false,"given":"Xingyu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"No-Joon","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan J.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6269-398X","authenticated-orcid":false,"given":"Anjun","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jay K.","family":"Mandula","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amir","family":"Yousif","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minh Quynh May","family":"Le","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianying","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fengxia","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bella","family":"Weaver","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9283-6144","authenticated-orcid":false,"given":"Heng-Yi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang-Yun","family":"Lay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debasish","family":"Sundi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3062-9777","authenticated-orcid":false,"given":"Maria","family":"Velegraki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Payton","family":"Weltge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juanita L.","family":"Merchant","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark P.","family":"Rubinstein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3004-072X","authenticated-orcid":false,"given":"Kenneth J.","family":"Oestreich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chan-Wang Jerry","family":"Lio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9816-4286","authenticated-orcid":false,"given":"Hazem E.","family":"Ghoneim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8708-8206","authenticated-orcid":false,"given":"Dan","family":"Theodorescu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Xin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3264-8392","authenticated-orcid":false,"given":"Qin","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1562-9218","authenticated-orcid":false,"given":"Weiguo","family":"Cui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4603-927X","authenticated-orcid":false,"given":"Zihai","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"2461_CR1","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":"2461_CR2","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/nri3862","volume":"15","author":"EJ Wherry","year":"2015","unstructured":"Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486\u2013499 (2015).","journal-title":"Nat. Rev. Immunol."},{"key":"2461_CR3","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1038\/nature19317","volume":"537","author":"R He","year":"2016","unstructured":"He, R. et al. Follicular CXCR5- expressing CD8+ T cells curtail chronic viral infection. Nature 537, 412\u2013416 (2016).","journal-title":"Nature"},{"key":"2461_CR4","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nature19330","volume":"537","author":"SJ Im","year":"2016","unstructured":"Im, S. J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417\u2013421 (2016).","journal-title":"Nature"},{"key":"2461_CR5","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1146\/annurev-immunol-041015-055318","volume":"37","author":"LM McLane","year":"2019","unstructured":"McLane, L. M., Abdel-Hakeem, M. S. & Wherry, E. J. CD8 T cell exhaustion during chronic viral infection and cancer. Annu. Rev. Immunol. 37, 457\u2013495 (2019).","journal-title":"Annu. Rev. Immunol."},{"key":"2461_CR6","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1038\/ni.2035","volume":"12","author":"EJ Wherry","year":"2011","unstructured":"Wherry, E. J. T cell exhaustion. Nat. Immunol. 12, 492\u2013499 (2011).","journal-title":"Nat. Immunol."},{"key":"2461_CR7","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1016\/j.immuni.2019.10.009","volume":"51","author":"R Zander","year":"2019","unstructured":"Zander, R. et al. CD4+ T cell help is required for the formation of a cytolytic CD8+ T cell subset that protects against chronic infection and cancer. Immunity 51, 1028\u20131042 (2019).","journal-title":"Immunity"},{"key":"2461_CR8","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1016\/j.immuni.2019.11.002","volume":"51","author":"WH Hudson","year":"2019","unstructured":"Hudson, W. H. et al. Proliferating transitory T cells with an effector-like transcriptional signature emerge from PD-1+ stem-like CD8+ T cells during chronic infection. Immunity 51, 1043\u20131058 (2019).","journal-title":"Immunity"},{"key":"2461_CR9","doi-asserted-by":"publisher","first-page":"e97828","DOI":"10.1172\/jci.insight.97828","volume":"3","author":"Y Yan","year":"2018","unstructured":"Yan, Y. et al. CX3CR1 identifies PD-1 therapy-responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy. JCI Insight 3, e97828 (2018).","journal-title":"JCI Insight"},{"key":"2461_CR10","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1016\/j.immuni.2019.09.013","volume":"51","author":"Z Chen","year":"2019","unstructured":"Chen, Z. et al. TCF-1-centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision. Immunity 51, 840\u2013855 (2019).","journal-title":"Immunity"},{"key":"2461_CR11","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.immuni.2016.07.021","volume":"45","author":"DT Utzschneider","year":"2016","unstructured":"Utzschneider, D. T. et al. T cell factor 1-expressing memory-like CD8+ T cells sustain the immune response to chronic viral infections. Immunity 45, 415\u2013427 (2016).","journal-title":"Immunity"},{"key":"2461_CR12","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/s41586-019-1326-9","volume":"571","author":"F Alfei","year":"2019","unstructured":"Alfei, F. et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 571, 265\u2013269 (2019).","journal-title":"Nature"},{"key":"2461_CR13","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1038\/s41586-019-1325-x","volume":"571","author":"O Khan","year":"2019","unstructured":"Khan, O. et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 571, 211\u2013218 (2019).","journal-title":"Nature"},{"key":"2461_CR14","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/s41586-019-1324-y","volume":"571","author":"AC Scott","year":"2019","unstructured":"Scott, A. C. et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571, 270\u2013274 (2019).","journal-title":"Nature"},{"key":"2461_CR15","doi-asserted-by":"publisher","first-page":"2369","DOI":"10.1016\/j.immuni.2022.10.020","volume":"55","author":"S Lukhele","year":"2022","unstructured":"Lukhele, S. et al. The transcription factor IRF2 drives interferon-mediated CD8+ T cell exhaustion to restrict anti-tumor immunity. Immunity 55, 2369\u20132385 (2022).","journal-title":"Immunity"},{"key":"2461_CR16","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1016\/j.immuni.2017.11.021","volume":"47","author":"K Man","year":"2017","unstructured":"Man, K. et al. Transcription factor IRF4 promotes CD8+ T cell exhaustion and limits the development of memory-like T cells during chronic infection. Immunity 47, 1129\u20131141 (2017).","journal-title":"Immunity"},{"key":"2461_CR17","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1038\/s41586-019-0985-x","volume":"567","author":"J Chen","year":"2019","unstructured":"Chen, J. et al. NR4A transcription factors limit CAR T cell function in solid tumours. Nature 567, 530\u2013534 (2019).","journal-title":"Nature"},{"key":"2461_CR18","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.immuni.2015.01.006","volume":"42","author":"GJ Martinez","year":"2015","unstructured":"Martinez, G. J. et al. The transcription factor NFAT promotes exhaustion of activated CD8+ T cells. Immunity 42, 265\u2013278 (2015).","journal-title":"Immunity"},{"key":"2461_CR19","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1038\/s41590-021-00965-7","volume":"22","author":"Y Chen","year":"2021","unstructured":"Chen, Y. et al. BATF regulates progenitor to cytolytic effector CD8+ T cell transition during chronic viral infection. Nat. Immunol. 22, 996\u20131007 (2021).","journal-title":"Nat. Immunol."},{"key":"2461_CR20","doi-asserted-by":"publisher","DOI":"10.1126\/science.adn2337","volume":"387","author":"E Fagerberg","year":"2025","unstructured":"Fagerberg, E. et al. KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection. Science 387, eadn2337 (2025).","journal-title":"Science"},{"key":"2461_CR21","doi-asserted-by":"publisher","first-page":"1600","DOI":"10.1038\/s41590-022-01338-4","volume":"23","author":"JR Giles","year":"2022","unstructured":"Giles, J. R. et al. Shared and distinct biological circuits in effector, memory and exhausted CD8+ T cells revealed by temporal single-cell transcriptomics and epigenetics. Nat. Immunol. 23, 1600\u20131613 (2022).","journal-title":"Nat. Immunol."},{"key":"2461_CR22","doi-asserted-by":"publisher","first-page":"94330","DOI":"10.18632\/oncotarget.21698","volume":"8","author":"R Ocadiz-Ruiz","year":"2017","unstructured":"Ocadiz-Ruiz, R. et al. ZBP-89 function in colonic stem cells and during butyrate-induced senescence. Oncotarget 8, 94330\u201394344 (2017).","journal-title":"Oncotarget"},{"key":"2461_CR23","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adi9066","volume":"8","author":"LB Chopp","year":"2023","unstructured":"Chopp, L. B. et al. Zfp281 and Zfp148 control CD4+ T cell thymic development and T(H)2 functions. Sci. Immunol. 8, eadi9066 (2023).","journal-title":"Sci. Immunol."},{"key":"2461_CR24","doi-asserted-by":"publisher","first-page":"eabq2630","DOI":"10.1126\/sciimmunol.abq2630","volume":"7","author":"H Kwon","year":"2022","unstructured":"Kwon, H. et al. Androgen conspires with the CD8+ T cell exhaustion program and contributes to sex bias in cancer. Sci. Immunol. 7, eabq2630 (2022).","journal-title":"Sci. Immunol."},{"key":"2461_CR25","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1016\/j.immuni.2020.04.014","volume":"52","author":"JC Beltra","year":"2020","unstructured":"Beltra, J. C. et al. Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity 52, 825\u2013841 (2020).","journal-title":"Immunity"},{"key":"2461_CR26","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1038\/ni.2745","volume":"14","author":"CN Skon","year":"2013","unstructured":"Skon, C. N. et al. Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells. Nat. Immunol. 14, 1285\u20131293 (2013).","journal-title":"Nat. Immunol."},{"key":"2461_CR27","doi-asserted-by":"publisher","first-page":"4292","DOI":"10.1073\/pnas.1917298117","volume":"117","author":"SJ Im","year":"2020","unstructured":"Im, S. J., Konieczny, B. T., Hudson, W. H., Masopust, D. & Ahmed, R. PD-1+ stemlike CD8 T cells are resident in lymphoid tissues during persistent LCMV infection. Proc. Natl Acad. Sci. USA 117, 4292\u20134299 (2020).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2461_CR28","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1038\/s41590-025-02276-7","volume":"26","author":"C Tsui","year":"2025","unstructured":"Tsui, C. et al. Lymph nodes fuel KLF2-dependent effector CD8+ T cell differentiation during chronic infection and checkpoint blockade. Nat. Immunol. 26, 1752\u20131765 (2025).","journal-title":"Nat. Immunol."},{"key":"2461_CR29","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1038\/s41590-019-0312-6","volume":"20","author":"BC Miller","year":"2019","unstructured":"Miller, B. C. et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 20, 326\u2013336 (2019).","journal-title":"Nat. Immunol."},{"key":"2461_CR30","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/s41590-023-01685-w","volume":"25","author":"Z Zhu","year":"2024","unstructured":"Zhu, Z. et al. FOXP1 and KLF2 reciprocally regulate checkpoints of stem-like to effector transition in CAR T cells. Nat. Immunol. 25, 117\u2013128 (2024).","journal-title":"Nat. Immunol."},{"key":"2461_CR31","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1038\/nature04444","volume":"439","author":"DL Barber","year":"2006","unstructured":"Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682\u2013687 (2006).","journal-title":"Nature"},{"key":"2461_CR32","doi-asserted-by":"publisher","first-page":"1550","DOI":"10.1038\/s41591-023-02371-y","volume":"29","author":"Y Chu","year":"2023","unstructured":"Chu, Y. et al. Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance. Nat. Med. 29, 1550\u20131562 (2023).","journal-title":"Nat. Med."},{"key":"2461_CR33","volume":"5","author":"B Gyorffy","year":"2024","unstructured":"Gyorffy, B. Integrated analysis of public datasets for the discovery and validation of survival-associated genes in solid tumors. Innovation (Camb.) 5, 100625 (2024).","journal-title":"Innovation (Camb.)"},{"key":"2461_CR34","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/s41586-022-05400-x","volume":"612","author":"R Xue","year":"2022","unstructured":"Xue, R. et al. Liver tumour immune microenvironment subtypes and neutrophil heterogeneity. Nature 612, 141\u2013147 (2022).","journal-title":"Nature"},{"key":"2461_CR35","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1038\/s41401-023-01079-6","volume":"44","author":"SA Kovacs","year":"2023","unstructured":"Kovacs, S. A., Fekete, J. T. & Gyorffy, B. Predictive biomarkers of immunotherapy response with pharmacological applications in solid tumors. Acta Pharmacol. Sin. 44, 1879\u20131889 (2023).","journal-title":"Acta Pharmacol. Sin."},{"key":"2461_CR36","doi-asserted-by":"publisher","first-page":"1550","DOI":"10.1038\/s41591-018-0136-1","volume":"24","author":"P Jiang","year":"2018","unstructured":"Jiang, P. et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat. Med. 24, 1550\u20131558 (2018).","journal-title":"Nat. Med."},{"key":"2461_CR37","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1016\/j.ccell.2021.03.007","volume":"39","author":"C Krishna","year":"2021","unstructured":"Krishna, C. et al. Single-cell sequencing links multiregional immune landscapes and tissue-resident T cells in ccRCC to tumor topology and therapy efficacy. Cancer Cell 39, 662\u2013677 (2021).","journal-title":"Cancer Cell"},{"key":"2461_CR38","doi-asserted-by":"publisher","first-page":"1848","DOI":"10.1038\/s41591-022-01959-0","volume":"28","author":"NJ Haradhvala","year":"2022","unstructured":"Haradhvala, N. J. et al. Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma. Nat. Med. 28, 1848\u20131859 (2022).","journal-title":"Nat. Med."},{"key":"2461_CR39","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-70824-2","volume":"10","author":"ZV Zou","year":"2020","unstructured":"Zou, Z. V. et al. Genomic profiling of the transcription factor Zfp148 and its impact on the p53 pathway. Sci. Rep. 10, 14156 (2020).","journal-title":"Sci. Rep."},{"key":"2461_CR40","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1161\/ATVBAHA.118.311136","volume":"39","author":"M Salmon","year":"2019","unstructured":"Salmon, M. et al. ZFP148 (zinc-finger protein 148) binds cooperatively with NF-1 (neurofibromin 1) to inhibit smooth muscle marker gene expression during abdominal aortic aneurysm formation. Arterioscler Thromb. Vasc. Biol. 39, 73\u201388 (2019).","journal-title":"Arterioscler Thromb. Vasc. Biol."},{"key":"2461_CR41","doi-asserted-by":"publisher","first-page":"2675","DOI":"10.1128\/MCB.01945-07","volume":"28","author":"AJ Woo","year":"2008","unstructured":"Woo, A. J. et al. Identification of ZBP-89 as a novel GATA-1-associated transcription factor involved in megakaryocytic and erythroid development. Mol. Cell Biol. 28, 2675\u20132689 (2008).","journal-title":"Mol. Cell Biol."},{"key":"2461_CR42","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1677\/JOE-09-0266","volume":"204","author":"M Udelhoven","year":"2010","unstructured":"Udelhoven, M., Pasieka, M., Leeser, U., Krone, W. & Schubert, M. Neuronal insulin receptor substrate 2 (IRS2) expression is regulated by ZBP89 and SP1 binding to the IRS2 promoter. J. Endocrinol. 204, 199\u2013208 (2010).","journal-title":"J. Endocrinol."},{"key":"2461_CR43","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.1126\/science.aar4060","volume":"359","author":"A Ribas","year":"2018","unstructured":"Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350\u20131355 (2018).","journal-title":"Science"},{"key":"2461_CR44","doi-asserted-by":"publisher","first-page":"4336","DOI":"10.1016\/j.cell.2024.07.018","volume":"187","author":"SF Ngiow","year":"2024","unstructured":"Ngiow, S. F. et al. LAG-3 sustains TOX expression and regulates the CD94\/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity. Cell 187, 4336\u20134354 (2024).","journal-title":"Cell"},{"key":"2461_CR45","doi-asserted-by":"publisher","first-page":"4355","DOI":"10.1016\/j.cell.2024.07.016","volume":"187","author":"LP Andrews","year":"2024","unstructured":"Andrews, L. P. et al. LAG-3 and PD-1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN-gamma-dependent anti-tumor immunity. Cell 187, 4355\u20134372 (2024).","journal-title":"Cell"},{"key":"2461_CR46","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1038\/nature22079","volume":"545","author":"AC Huang","year":"2017","unstructured":"Huang, A. C. et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545, 60\u201365 (2017).","journal-title":"Nature"},{"key":"2461_CR47","doi-asserted-by":"publisher","first-page":"4993","DOI":"10.1073\/pnas.1705327114","volume":"114","author":"AO Kamphorst","year":"2017","unstructured":"Kamphorst, A. O. et al. Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients. Proc. Natl Acad. Sci. USA 114, 4993\u20134998 (2017).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2461_CR48","doi-asserted-by":"publisher","first-page":"8623","DOI":"10.1073\/pnas.0809818106","volume":"106","author":"SN Mueller","year":"2009","unstructured":"Mueller, S. N. & Ahmed, R. High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc. Natl Acad. Sci. USA 106, 8623\u20138628 (2009).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2461_CR49","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01062-w","volume":"8","author":"M Sade-Feldman","year":"2017","unstructured":"Sade-Feldman, M. et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat. Commun. 8, 1136 (2017).","journal-title":"Nat. Commun."},{"key":"2461_CR50","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1038\/s41586-022-05105-1","volume":"609","author":"C Tsui","year":"2022","unstructured":"Tsui, C. et al. MYB orchestrates T cell exhaustion and response to checkpoint inhibition. Nature 609, 354\u2013360 (2022).","journal-title":"Nature"},{"key":"2461_CR51","doi-asserted-by":"publisher","first-page":"e20210116","DOI":"10.1084\/jem.20210116","volume":"219","author":"M Evrard","year":"2022","unstructured":"Evrard, M. Sphingosine 1-phosphate receptor 5 (S1PR5) regulates the peripheral retention of tissue-resident lymphocytes. J. Exp. Med. 219, e20210116 (2022).","journal-title":"J. Exp. Med."},{"key":"2461_CR52","doi-asserted-by":"publisher","first-page":"1583","DOI":"10.1016\/j.ccell.2022.11.001","volume":"40","author":"RY Li","year":"2022","unstructured":"Li, R. Y. et al. Mapping single-cell transcriptomes in the intra-tumoral and associated territories of kidney cancer. Cancer Cell 40, 1583\u20131599 (2022).","journal-title":"Cancer Cell"},{"key":"2461_CR53","doi-asserted-by":"publisher","first-page":"e2103240118","DOI":"10.1073\/pnas.2103240118","volume":"118","author":"YP Zhang","year":"2021","unstructured":"Zhang, Y. P. et al. Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response. Proc. Natl Acad. Sci. USA 118, e2103240118 (2021).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2461_CR54","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1038\/s41467-023-36296-4","volume":"14","author":"G Werba","year":"2023","unstructured":"Werba, G. et al. Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment. Nat. Commun. 14, 797 (2023).","journal-title":"Nat. Commun."},{"key":"2461_CR55","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1016\/j.ccell.2019.08.007","volume":"36","author":"LC Ma","year":"2019","unstructured":"Ma, L. C. et al. Tumor cell biodiversity drives microenvironmental reprogramming in liver cancer. Cancer Cell 36, 418\u2013430 (2019).","journal-title":"Cancer Cell"},{"key":"2461_CR56","doi-asserted-by":"publisher","first-page":"4924","DOI":"10.1016\/j.molcel.2021.10.013","volume":"81","author":"MJ Regner","year":"2021","unstructured":"Regner, M. J. et al. A multi-omic single-cell landscape of human gynecologic malignancies. Mol. Cell 81, 4924\u20134941 (2021).","journal-title":"Mol. Cell"},{"key":"2461_CR57","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1038\/s41422-020-0374-x","volume":"30","author":"YP Chen","year":"2020","unstructured":"Chen, Y. P. et al. Single-cell transcriptomics reveals regulators underlying immune cell diversity and immune subtypes associated with prognosis in nasopharyngeal carcinoma. Cell Res. 30, 1024\u20131042 (2020).","journal-title":"Cell Res."},{"key":"2461_CR58","doi-asserted-by":"publisher","first-page":"3590","DOI":"10.1158\/1078-0432.CCR-22-0296","volume":"28","author":"JF Xu","year":"2022","unstructured":"Xu, J. F. et al. Single-cell RNA sequencing reveals the tissue architecture in human high-grade serous ovarian cancer. Clin. Cancer Res. 28, 3590\u20133602 (2022).","journal-title":"Clin. Cancer Res."},{"key":"2461_CR59","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1038\/s42003-022-04142-w","volume":"5","author":"CB Li","year":"2022","unstructured":"Li, C. B. Single-cell transcriptomics reveals cellular heterogeneity and molecular stratification of cervical cancer. Commun. Biol. 5, 1208 (2022).","journal-title":"Commun. Biol."},{"key":"2461_CR60","doi-asserted-by":"publisher","first-page":"6619","DOI":"10.1038\/s41467-022-34395-2","volume":"13","author":"H Luo","year":"2022","unstructured":"Luo, H. Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment. Nat. Commun. 13, 6619 (2022).","journal-title":"Nat. Commun."},{"key":"2461_CR61","doi-asserted-by":"publisher","first-page":"2640","DOI":"10.1158\/1078-0432.CCR-19-3231","volume":"26","author":"A Sathe","year":"2020","unstructured":"Sathe, A. et al. Single-cell genomic characterization reveals the cellular reprogramming of the gastric tumor microenvironment. Clin. Cancer Res. 26, 2640\u20132653 (2020).","journal-title":"Clin. Cancer Res."},{"key":"2461_CR62","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16164-1","volume":"11","author":"N Kim","year":"2020","unstructured":"Kim, N. et al. Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma. Nat. Commun. 11, 2285 (2020).","journal-title":"Nat. Commun."},{"key":"2461_CR63","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.1038\/s41591-018-0096-5","volume":"24","author":"D Lambrechts","year":"2018","unstructured":"Lambrechts, D. et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat. Med. 24, 1277\u20131289 (2018).","journal-title":"Nat. Med."},{"key":"2461_CR64","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1038\/s41556-020-00613-6","volume":"23","author":"SJ Chen","year":"2021","unstructured":"Chen, S. J. et al. Single-cell analysis reveals transcriptomic remodellings in distinct cell types that contribute to human prostate cancer progression. Nat. Cell Biol. 23, 87\u201398 (2021).","journal-title":"Nat. Cell Biol."},{"key":"2461_CR65","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1186\/s12943-020-01264-9","volume":"19","author":"XS Ma","year":"2020","unstructured":"Ma, X. S. et al. Identification of a distinct luminal subgroup diagnosing and stratifying early stage prostate cancer by tissue-based single-cell RNA sequencing. Mol. Cancer 19, 147 (2020).","journal-title":"Mol. Cancer"},{"key":"2461_CR66","doi-asserted-by":"publisher","first-page":"eabf3657","DOI":"10.1126\/sciadv.abf3657","volume":"7","author":"H Luo","year":"2021","unstructured":"Luo, H. et al. Characterizing dedifferentiation of thyroid cancer by integrated analysis. Sci. Adv. 7, eabf3657 (2021).","journal-title":"Sci. Adv."},{"key":"2461_CR67","doi-asserted-by":"publisher","first-page":"5077","DOI":"10.1038\/s41467-020-18916-5","volume":"11","author":"ZH Chen","year":"2020","unstructured":"Chen, Z. H. Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma. Nat. Commun. 11, 5077 (2020).","journal-title":"Nat. Commun."},{"key":"2461_CR68","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1038\/s41422-020-0355-0","volume":"30","author":"JB Qian","year":"2020","unstructured":"Qian, J. B. et al. A pan-cancer blueprint of the heterogeneous tumor microenvironment revealed by single-cell profiling. Cell Res. 30, 745\u2013762 (2020).","journal-title":"Cell Res."},{"key":"2461_CR69","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1016\/j.jhep.2020.05.039","volume":"73","author":"M Zhang","year":"2020","unstructured":"Zhang, M. et al. Single-cell transcriptomic architecture and intercellular crosstalk of human intrahepatic cholangiocarcinoma. J. Hepatol. 73, 1118\u20131130 (2020).","journal-title":"J. Hepatol."},{"key":"2461_CR70","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1038\/s41422-019-0195-y","volume":"29","author":"JY Peng","year":"2019","unstructured":"Peng, J. Y. et al. Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma. Cell Res. 29, 725\u2013738 (2019).","journal-title":"Cell Res."},{"key":"2461_CR71","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1186\/s13073-020-00776-9","volume":"12","author":"W Lin","year":"2020","unstructured":"Lin, W. Single-cell transcriptome analysis of tumor and stromal compartments of pancreatic ductal adenocarcinoma primary tumors and metastatic lesions. Genome Med. 12, 80 (2020).","journal-title":"Genome Med."},{"key":"2461_CR72","doi-asserted-by":"publisher","first-page":"73","DOI":"10.2307\/2532740","volume":"48","author":"B Lausen","year":"1992","unstructured":"Lausen, B. & Schumacher, M. Maximally selected rank statistics. Biometrics 48, 73\u201385 (1992).","journal-title":"Biometrics"},{"key":"2461_CR73","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1038\/s41586-025-09539-1","volume":"647","author":"Y Wang","year":"2025","unstructured":"Wang, Y. et al. Proteotoxic stress response drives T cell exhaustion and immune evasion. Nature 647, 1025\u20131035 (2025).","journal-title":"Nature"}],"container-title":["Nature Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41590-026-02461-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41590-026-02461-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41590-026-02461-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T17:03:02Z","timestamp":1775062982000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41590-026-02461-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,27]]},"references-count":73,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["2461"],"URL":"https:\/\/doi.org\/10.1038\/s41590-026-02461-2","relation":{},"ISSN":["1529-2908","1529-2916"],"issn-type":[{"value":"1529-2908","type":"print"},{"value":"1529-2916","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,27]]},"assertion":[{"value":"21 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Z.L. serves as a member of scientific advisory boards for HanchorBio. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}