{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T17:40:54Z","timestamp":1787938854664,"version":"build-2784847793"},"reference-count":42,"publisher":"American Society for Clinical Investigation","issue":"6","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"vor","delay-in-days":46,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Health Research Institutes (NHRI), Taiwan","award":["IM-113-SP-02"],"award-info":[{"award-number":["IM-113-SP-02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,16]]},"abstract":"<jats:p>\n                    MAP kinase kinase kinase kinase (MAP4K) family kinases are key kinases for T cell\u2013mediated immune responses; however, in vivo roles of MAP4K2 in immune regulation remain unclear. Using T cell\u2013specific\n                    <jats:italic>Map4k2<\/jats:italic>\n                    conditional knockout (T-\n                    <jats:italic>Map4k2<\/jats:italic>\n                    cKO) mice, scRNA-seq, and mass spectrometry analysis, we found that MAP4K2 interacted with DDX39B, induced forkhead box protein P3\n                    <jats:italic>(FOXP3)<\/jats:italic>\n                    gene expression, and promoted Treg differentiation. Mechanistically, MAP4K2 directly phosphorylated the DEAD box protein DDX39B, leading to DDX39B nuclear translocation and subsequent\n                    <jats:italic>Foxp3<\/jats:italic>\n                    RNA splicing. MAP4K2-induced\n                    <jats:italic>FOXP3<\/jats:italic>\n                    mRNA levels were abolished in\n                    <jats:italic>DDX39B<\/jats:italic>\n                    knockout T cells. Furthermore, T-\n                    <jats:italic>Map4k2<\/jats:italic>\n                    cKO mice displayed the reduction of Treg population and the sustained inflammation during remission phase of EAE autoimmune disease model. Remarkably, the anti\u2013PD-1 immunotherapeutic effect on pancreatic cancer was significantly improved in T-\n                    <jats:italic>Map4k2<\/jats:italic>\n                    cKO mice, Treg-specific\n                    <jats:italic>Map4k2<\/jats:italic>\n                    -deficient mice, adoptively transferred chimeric mice, or MAP4K2-inhibitor\u2013treated mice. Consistently, scRNA-seq analysis of patients with pancreatic cancer showed increased\n                    <jats:italic>MAP4K2<\/jats:italic>\n                    levels in infiltrating Treg cells. Collectively, MAP4K2 promotes Treg differentiation by inducing DDX39B nuclear translocation, leading to the attenuation of antitumor immunity.\n                  <\/jats:p>","DOI":"10.1172\/jci196379","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T18:23:47Z","timestamp":1769797427000},"source":"Crossref","is-referenced-by-count":1,"title":["MAP4K2 suppresses antitumor immunity in a pancreatic cancer model by promoting Treg differentiation"],"prefix":"10.1172","volume":"136","author":[{"given":"Huai-Chia","family":"Chuang","sequence":"first","affiliation":[{"name":"Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Wen","family":"Wang","sequence":"additional","affiliation":[{"name":"Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8038-3771","authenticated-orcid":true,"given":"Chia-Hsin","family":"Hsueh","sequence":"additional","affiliation":[{"name":"Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Zhi","family":"Xiao","sequence":"additional","affiliation":[{"name":"Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Yi","family":"Tsai","sequence":"additional","affiliation":[{"name":"Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pu-Ming","family":"Hsu","sequence":"additional","affiliation":[{"name":"Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn L.","family":"Tan","sequence":"additional","affiliation":[{"name":"Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsien-Yi","family":"Chiu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4969-3170","authenticated-orcid":true,"given":"Tse-Hua","family":"Tan","sequence":"additional","affiliation":[{"name":"Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,1,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2023.01.004"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-024-00994-x"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.03100"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxae049"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-022-00818-z"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00530"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/ni1416"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2121"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5602"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/377750a0"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2023.2280876"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020006334"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.18.9687"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ai.2015.09.006"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1101\/gad.10.18.2251"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00028.2011"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1202757109"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0501675102"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.76927"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0120-4"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-4100"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2023.05.036"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.02.014"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36296-4"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022671"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-01096-7"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae431"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.7150\/thno.63743"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/art.41920"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202215904"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1172\/JCI166269"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-44843-w"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201900105RR"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s11605-015-2985-y"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15959-6"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aat5401"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1300989"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.7150\/thno.72148"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200210140"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-1402"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2021-221010"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth947"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/196379\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T16:42:49Z","timestamp":1779208969000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/196379"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,29]]},"references-count":42,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3,16]]},"published-print":{"date-parts":[[2026,3,16]]}},"alternative-id":["10.1172\/JCI196379"],"URL":"https:\/\/doi.org\/10.1172\/jci196379","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,29]]},"article-number":"e196379"}}