{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T18:02:33Z","timestamp":1789322553531,"version":"build-2803163510"},"reference-count":111,"publisher":"Wiley","issue":"29","license":[{"start":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T00:00:00Z","timestamp":1717372800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Distant metastasis, the leading cause of cancer death, is efficiently kept in check by immune surveillance. Studies have uncovered peripheral natural killer (NK) cells as key antimetastatic effectors and their dysregulation during metastasis. However, the molecular mechanism governing NK cell dysfunction links to metastasis remains elusive. Herein, <jats:italic>MAP4K1<\/jats:italic> encoding HPK1 is aberrantly overexpressed in dysfunctional NK cells in the periphery and the metastatic site. Conditional HPK1 overexpression in NK cells suffices to exacerbate melanoma lung metastasis but not primary tumor growth. Conversely, <jats:italic>MAP4K1<\/jats:italic>\u2010deficient mice are resistant to metastasis and further protected by combined immune\u2010checkpoint inhibitors. Mechanistically, HPK1 restrains NK cell cytotoxicity and expansion via activating receptors. Likewise, HPK1 limits human NK cell activation and associates with melanoma NK cell dysfunction couples to TGF\u2010\u03b21 and patient response to immune checkpoint therapy. Thus, HPK1 is an intracellular checkpoint controlling NK\u2010target cell responses, which is dysregulated and hijacked by tumors during metastatic progression.<\/jats:p>","DOI":"10.1002\/advs.202400920","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T05:47:10Z","timestamp":1717393630000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["HPK1 Dysregulation\u2010Associated NK Cell Dysfunction and Defective Expansion Promotes Metastatic Melanoma Progression"],"prefix":"10.1002","volume":"11","author":[{"given":"Woo Seon","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Microbiology Stem Cell Immunomodulation Research Center Asan Medical Center University of Ulsan College of Medicine Seoul 05505 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyung\u2010Joon","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Microbiology Stem Cell Immunomodulation Research Center Asan Medical Center University of Ulsan College of Medicine Seoul 05505 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunbi","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Microbiology Stem Cell Immunomodulation Research Center Asan Medical Center University of Ulsan College of Medicine Seoul 05505 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haeun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Microbiology Stem Cell Immunomodulation Research Center Asan Medical Center University of Ulsan College of Medicine Seoul 05505 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Min","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Microbiology Stem Cell Immunomodulation Research Center Asan Medical Center University of Ulsan College of Medicine Seoul 05505 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyo Jin","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Microbiology Stem Cell Immunomodulation Research Center Asan Medical Center University of Ulsan College of Medicine Seoul 05505 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Ji","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Dermatology Asan Institute for Life Sciences Asan Medical Center University of Ulsan College of Medicine Seoul 05505 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myoung Eun","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Dermatology Asan Institute for Life Sciences Asan Medical Center University of Ulsan College of Medicine Seoul 05505 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Hoon","family":"Sung","sequence":"additional","affiliation":[{"name":"Department of Cell and Genetic Engineering Asan Medical Center University of Ulsan College of Medicine Seoul 05505 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong Hyun","family":"Won","sequence":"additional","affiliation":[{"name":"Department of Dermatology Asan Institute for Life Sciences Asan Medical Center University of Ulsan College of Medicine Seoul 05505 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang Ohk","family":"Sung","sequence":"additional","affiliation":[{"name":"Department of Pathology Asan Medical Institute of Convergence Science and Technology Asan Medical Center University of Ulsan College of Medicine Seoul 05505 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5729-6581","authenticated-orcid":false,"given":"Hun Sik","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Microbiology Stem Cell Immunomodulation Research Center Asan Medical Center University of Ulsan College of Medicine Seoul 05505 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,3]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.03.003"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-021-00347-z"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2019.06.002"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-01195-4"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.07.001"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3394"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI42002"},{"key":"e_1_2_9_7_2","doi-asserted-by":"publisher","DOI":"10.7150\/jca.13098"},{"key":"e_1_2_9_7_3","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00689-z"},{"key":"e_1_2_9_7_4","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-1808"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0892-6"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2015.5"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0061-z"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-101921-044122"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-020711-075005"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.06.009"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-0272-z"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5539"},{"key":"e_1_2_9_15_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102461"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI97611"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI45816"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01354"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-0655"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.03.9594"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1177\/030089160108700509"},{"key":"e_1_2_9_21_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-1965"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-4179"},{"key":"e_1_2_9_23_1","first-page":"21","author":"Kim J. M.","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature04186"},{"key":"e_1_2_9_24_2","first-page":"820","volume":"142","author":"Deng W.","year":"2017","journal-title":"Analyst"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abc4882"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201444643"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1763"},{"key":"e_1_2_9_27_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02785"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aau6085"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0611655104"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(02)00302-3"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1176"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80192-2"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1416"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.08.001"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.55122"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-07-2316"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgh261"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2467"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2016.10.022"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1112064108"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200424877"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15776"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01869"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-10-187179"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901520"},{"key":"e_1_2_9_45_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-12-474361"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2006.00450.x"},{"key":"e_1_2_9_46_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0605978104"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20062066"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M101485200"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.09.012"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.02.004"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2002754"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-009-0761-0"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-019-1259-z"},{"key":"e_1_2_9_53_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1910836"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11686"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.4161\/onci.26011"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.155.3.1066"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aad1884"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0500"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.07.034"},{"key":"e_1_2_9_60_1","first-page":"132","author":"Chan I. S.","year":"2022","journal-title":"J. Clin. Invest."},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.371062"},{"key":"e_1_2_9_61_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0802631"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0900457106"},{"key":"e_1_2_9_62_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1996.tb01093.x"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-08-303123"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.08.015"},{"key":"e_1_2_9_65_1","volume":"16","author":"McAllister S. S.","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"e_1_2_9_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1507"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2011.09.006"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3578"},{"key":"e_1_2_9_67_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0085942"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.12.7335"},{"key":"e_1_2_9_68_2","doi-asserted-by":"publisher","DOI":"10.1080\/08977194.2022.2124915"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02041"},{"key":"e_1_2_9_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.09.020"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.03.024"},{"key":"e_1_2_9_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.10.020"},{"key":"e_1_2_9_70_3","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-019-0719-5"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001402"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aat7527"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2857"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.163394.113"},{"key":"e_1_2_9_75_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3614"},{"key":"e_1_2_9_76_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI92958"},{"key":"e_1_2_9_77_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1923"},{"key":"e_1_2_9_78_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq033"},{"key":"e_1_2_9_79_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2004-5-10-r80"},{"key":"e_1_2_9_80_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.10.038"},{"key":"e_1_2_9_80_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad0501"},{"key":"e_1_2_9_81_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-0355-0"},{"key":"e_1_2_9_82_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-3231"},{"key":"e_1_2_9_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.05.039"},{"key":"e_1_2_9_84_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-019-0195-y"},{"key":"e_1_2_9_85_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-0636-z"},{"key":"e_1_2_9_86_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.04.048"},{"key":"e_1_2_9_87_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_9_88_1","doi-asserted-by":"publisher","DOI":"10.1089\/cmb.2020.0426"},{"key":"e_1_2_9_89_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-7"},{"key":"e_1_2_9_90_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0276-y"},{"key":"e_1_2_9_91_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4402"},{"key":"e_1_2_9_92_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3470"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202400920","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T18:40:13Z","timestamp":1759776013000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202400920"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,3]]},"references-count":111,"journal-issue":{"issue":"29","published-print":{"date-parts":[[2024,8]]}},"alternative-id":["10.1002\/advs.202400920"],"URL":"https:\/\/doi.org\/10.1002\/advs.202400920","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,3]]},"assertion":[{"value":"2024-01-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2400920"}}