{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:28:54Z","timestamp":1785414534534,"version":"3.56.0"},"reference-count":58,"publisher":"National Academy of Sciences","issue":"25","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,6,23]]},"abstract":"<jats:p>Immune-mediated killing triggers dynamic transcriptional adaptations in tumor cells that can reciprocally regulate the cytolytic process. Unraveling such feedback mechanisms is crucial for advancing cancer immunotherapy. Here, we identified tissue factor pathway inhibitor 2 (TFPI2) as a central node in natural killer (NK)\u2013glioblastoma cross talk. Using transcriptomic and functional approaches, we demonstrated that NK cell attack induces TFPI2 expression in glioblastoma cells via IL1\u03b2- and TNF\u03b1-driven activation of NF\u03baB signaling. TFPI2 not only restrains tumor proliferation by suppressing the POU2F2\u2013CCND1 axis but also enhances NK cytotoxicity through two complementary mechanisms: It supports optimal ICAM1 expression to promote NK\u2013tumor adhesion, and it selectively represses the immune checkpoint molecule SIGLEC15, restoring NK cell effector function. In vivo, loss of TFPI2 accelerates glioblastoma progression and abrogates the efficacy of adoptive NK cell therapy in a context-dependent manner; the functionality is likely restricted to tumors retaining the capacity for TFPI2 induction upon inflammatory stimuli. Our findings identified the TFPI2\u2013ICAM1 and TFPI2\u2013SIGLEC15 axes as conditional regulators of immune\u2013tumor adhesion and checkpoint control, supporting TFPI2 as a candidate therapeutic target for a subset of glioblastomas amenable to inflammatory reprogramming.<\/jats:p>","DOI":"10.1073\/pnas.2529973123","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T18:09:31Z","timestamp":1781806171000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["TFPI2 promotes NK cell\u2013mediated glioblastoma killing through adhesion and checkpoint control"],"prefix":"10.1073","volume":"123","author":[{"given":"Dongpeng","family":"Zheng","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University","place":["Tianjin, China"]},{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Synthetic Biology, Tianjin University","place":["Tianjin, China"]},{"name":"The State Key Laboratory of Neurology and Oncology Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing Simcere Medical Laboratory Science Co., Ltd.,","place":["Nanjing, China"]},{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, Tianjin University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1670-6062","authenticated-orcid":false,"given":"Fengqi","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University","place":["Tianjin, China"]},{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Synthetic Biology, Tianjin University","place":["Tianjin, China"]},{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, Tianjin University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuang","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University","place":["Tianjin, China"]},{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, Tianjin University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunyi","family":"Dong","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University","place":["Tianjin, China"]},{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, Tianjin University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuebin","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00q6wbs64","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Neurosurgery, Tianjin Huanhu Hospital","place":["Tianjin, China"]},{"id":[{"id":"https:\/\/ror.org\/00q6wbs64","id-type":"ROR","asserted-by":"publisher"}],"name":"Tianjin Key Laboratory of Cerebral Blood Flow Reconstruction and Head and Neck Tumor New Technology Translation, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueren","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Respiratory Medicine, Jinnan Hospital, Tianjin University (Tianjin Jinnan Hospital)","place":["Tianjin, China"]},{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"Faculty of Medicine, Medical School of Tianjin University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3080-8732","authenticated-orcid":false,"given":"Jingyue","family":"Yang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00g51hv48","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Metastable Materials Science and Technology, Nano-biotechnology Key Lab of Hebei Province, Applying Chemistry Key Lab of Hebei Province, Yanshan University","place":["Qinhuangdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shouchun","family":"Peng","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Respiratory Medicine, Jinnan Hospital, Tianjin University (Tianjin Jinnan Hospital)","place":["Tianjin, China"]},{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"Faculty of Medicine, Medical School of Tianjin University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1810-2937","authenticated-orcid":false,"given":"Budong","family":"Chen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00q6wbs64","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Neurosurgery, Tianjin Huanhu Hospital","place":["Tianjin, China"]},{"id":[{"id":"https:\/\/ror.org\/00q6wbs64","id-type":"ROR","asserted-by":"publisher"}],"name":"Tianjin Key Laboratory of Cerebral Blood Flow Reconstruction and Head and Neck Tumor New Technology Translation, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5301-5799","authenticated-orcid":false,"given":"Shupeng","family":"Sun","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00q6wbs64","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Neurosurgery, Tianjin Huanhu Hospital","place":["Tianjin, China"]},{"id":[{"id":"https:\/\/ror.org\/00q6wbs64","id-type":"ROR","asserted-by":"publisher"}],"name":"Tianjin Key Laboratory of Cerebral Blood Flow Reconstruction and Head and Neck Tumor New Technology Translation, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5709-8497","authenticated-orcid":false,"given":"Zichuan","family":"Liu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University","place":["Tianjin, China"]},{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Synthetic Biology, Tianjin University","place":["Tianjin, China"]},{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, Tianjin University","place":["Tianjin, China"]},{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Respiratory Medicine, Jinnan Hospital, Tianjin University (Tianjin Jinnan Hospital)","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1022-1259","authenticated-orcid":false,"given":"Xin","family":"Mu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University","place":["Tianjin, China"]},{"name":"The State Key Laboratory of Neurology and Oncology Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing Simcere Medical Laboratory Science Co., Ltd.,","place":["Nanjing, China"]},{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"Tianjin University and Health-Biotech United Group Joint Laboratory of Innovative Drug Development and Translational Medicine, Tianjin University","place":["Tianjin, China"]},{"id":[{"id":"https:\/\/ror.org\/012tb2g32","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Respiratory Medicine, Jinnan Hospital, Tianjin University (Tianjin Jinnan Hospital)","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-025-02299-4"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1080\/10985549.2023.2210032"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-024-01226-x"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2025.03.004"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-02875-1"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2025.102353"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-061020-053702"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-022-00491-0"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01481-w"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/noajnl\/vdaf006"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.06.003"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28523-1"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa343"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32311-2"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI142116"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29469-0"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2111003119"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1413933111"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-008155"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1111\/jog.15770"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1186\/s10020-020-00158-2"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01605-y"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.10.030"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202551885"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.07.034"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.09.009"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2019.11.033"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20020317"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac1000"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2016.06.001"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000248731.55781.87"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-025-00958-7"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.01.022"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-03719-3"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04585-5"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2006.08.010"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-022-02309-7"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2023.1052959"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-23-0046"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/8696543"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx247"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2024.2376264"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25009-4"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2008.11.028"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2011.04.027"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.106984"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-024-06865-6"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2023.02.011"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201801227R"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1206695"},{"key":"e_1_3_4_51_2","first-page":"345","article-title":"Associations between TFPI-2 methylation and poor prognosis in glioblastomas","volume":"48","author":"Vaitkien\u0117 P.","year":"2012","unstructured":"P. Vaitkien\u0117, D. Skiriut\u0117, K. Skauminas, A. Tama\u0161auskas, Associations between TFPI-2 methylation and poor prognosis in glioblastomas. Medicina (Kaunas) 48, 345\u2013349 (2012).","journal-title":"Medicina (Kaunas)"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17704-5"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1297932"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-25-0323"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-21-0035"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.585034"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.00154"},{"key":"e_1_3_4_58_2","unstructured":"X. Mu TFPI2 orchestrates NK cell-mediated glioma killing through adhesion and checkpoint control. Genome Sequence Archive for Human. https:\/\/ngdc.cncb.ac.cn\/gsa-human\/browse\/HRA013588. Accessed 3 June 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2529973123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T18:09:46Z","timestamp":1781806186000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2529973123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,18]]},"references-count":58,"journal-issue":{"issue":"25","published-print":{"date-parts":[[2026,6,23]]}},"alternative-id":["10.1073\/pnas.2529973123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2529973123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,18]]},"assertion":[{"value":"2025-10-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2529973123"}}