{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:01:20Z","timestamp":1790784080133,"version":"4.1.0"},"reference-count":51,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25293095"],"award-info":[{"award-number":["25293095"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21H02988"],"award-info":[{"award-number":["21H02988"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22K19562"],"award-info":[{"award-number":["22K19562"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Activation of the RAS\/RAF\/ERK pathway is crucial for adaptive immunity. Here, we provide evidence that Sprouty\u2010related EVH1 domain containing 2 (SPRED2), an endogenous inhibitor of this pathway, negatively regulates CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell\u2010mediated antitumor immunity in breast cancer. In EO771 and 4T1 mouse models,\n                    <jats:italic>\n                      Spred2\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice exhibit reduced tumor growth, with lower endpoint lung metastatic burden in the 4T1 model, accompanied by increased T\u2010cell infiltration and activation.\n                    <jats:italic>\n                      Spred2\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    T cells show enhanced cytokine expression, proliferation, survival, in vitro cytotoxicity, and memory\u2010like phenotypes, particularly among CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Adoptive transfer of\n                    <jats:italic>\n                      Spred2\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells into tumor\u2010bearing wild\u2010type hosts similarly reduces endpoint lung metastatic burden. MEK inhibition with U0126 attenuates increased interferon\u2010gamma and granzyme B\u00a0expression in\n                    <jats:italic>\n                      Spred2\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Transcriptomic analyses reveal an inverse correlation between\n                    <jats:italic>SPRED2<\/jats:italic>\n                    expression and antitumor CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell states in both humans and mice. In tumor\u2010infiltrating T cells from patients with breast cancer,\n                    <jats:italic>\n                      SPRED2\n                      <jats:sup>low<\/jats:sup>\n                    <\/jats:italic>\n                    T cells show enriched effector and cytotoxicity programs and are associated with \u201cimmune\u2010hot\u201d tumors, whereas survival associations vary with CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell context. Collectively, these findings suggest that SPRED2 functions as a cell\u2010intrinsic negative regulator of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cell activation and highlight its potential as a therapeutic target to enhance T cell\u2013based cancer immunotherapy.\n                  <\/jats:p>","DOI":"10.1002\/advs.77909","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SPRED2 Negatively Regulates CD8\n                    <sup>+<\/sup>\n                    T Cell\u2010Mediated Antitumor Immunity in Breast Cancer"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2832-7096","authenticated-orcid":false,"given":"Miao","family":"Tian","sequence":"first","affiliation":[{"name":"Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3853-2075","authenticated-orcid":false,"given":"Teizo","family":"Yoshimura","sequence":"additional","affiliation":[{"name":"Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Oral Rehabilitation and Regenerative Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunning","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1884-8053","authenticated-orcid":false,"given":"Ziyi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Advanced International and Information Dentistry Faculty of Medicine Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4794-4837","authenticated-orcid":false,"given":"Masayoshi","family":"Fujisawa","sequence":"additional","affiliation":[{"name":"Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1557-1589","authenticated-orcid":false,"given":"Toshiaki","family":"Ohara","sequence":"additional","affiliation":[{"name":"Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5081-6089","authenticated-orcid":false,"given":"Akihiro","family":"Matsukawa","sequence":"additional","affiliation":[{"name":"Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010021\u201000823\u2010w"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.883733"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2014.12.082"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc\u20102022\u2010005845"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423\u2010020\u20100488\u20106"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20200661"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.341222.120"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24054996"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3892\/or.2020.7586"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25116269"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010020\u201073752\u20103"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep37531"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2021.03.014"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22094673"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3394"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz395"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41523\u2010023\u201000508\u20103"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12935\u2010020\u201001418\u20101"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.02.016"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms8458"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15082366"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14184397"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40425\u2010018\u20100401\u20103"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.4161\/onci.23972"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700242"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.15374"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201048704\u20104"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature22367"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201053593\u20108"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.12.012"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573\u2010018\u20100007\u2010y"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI96313"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201025962\u20100"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.CD\u201022\u20100475"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010023\u201001522\u20104"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01564"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0803853"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12030574"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.11.011"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201019\u20101868"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1026954"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00017"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0108914"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010024\u201002210\u20106"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046\u2010024\u201003195\u20105"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201018\u20100030"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.4049\/immunohorizons.1700055"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010022\u201005126\u2010w"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1801340115"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030830"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010017\u201017204\u20105"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.77909","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.77909","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.77909","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T15:06:12Z","timestamp":1790780772000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.77909"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,27]]},"references-count":51,"alternative-id":["10.1002\/advs.77909"],"URL":"https:\/\/doi.org\/10.1002\/advs.77909","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,27]]},"assertion":[{"value":"2025-12-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e77909"}}