{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T20:47:52Z","timestamp":1793998072537,"version":"4.8.0"},"reference-count":56,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Natural killer (NK) cell function is impaired in patients with chronic hepatitis B (CHB) infection; however, the underlying mechanisms are not fully understood. Here, we collected the blood samples from healthy donors (HDs) and patients with CHB, and then analyzed the characteristics of NK cells by RNA-seq analysis, flow cytometry, Seahorse assay. HBV-carrier mice were used to confirm the findings in vivo. We found that the dysfunction of NK cells in peripheral blood of patients with CHB was associated with the disturbance of glycolysis. Further investigation showed chronic HBV infection impaired the activation of mammalian target of rapamycin (mTOR) in NK cells, resulting in decreased expression of molecules involved in glycolysis, including HIF-1\u03b1 and GLUT1. Mechanistically, we found that HBsAg suppressed IL-15-triggered mTOR activity by competitively binding to the IL-15 receptor \u03b2 (IL-15R\u03b2, CD122) on NK cells, leading to the decreased expression of HIF-1\u03b1 and its downstream genes. Significantly, HBsAg neutralizing antibody intravenous injection or mTOR agonist MHY1485 intraperitoneal injection restored the IL-15\/mTOR signaling in NK cells of HBV-carrier mice, resulting in NK cell activation and HBV clearance. Further, transferring MHY1485-pretreated NK cells isolated from HBV-carrier mice displayed augmented anti-HBV effects in recipient HBV-carrier mice. These findings reveal a new mechanism by which chronic HBV infection induces NK cell dysfunction, and highlight the potential of mTOR activation and HBsAg clearance as therapeutic strategies for CHB treatment via recovering NK cell immune functions.<\/jats:p>","DOI":"10.1038\/s41419-025-08069-y","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T06:54:13Z","timestamp":1760338453000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Chronic HBV infection impairs the glucose metabolism and effector function of NK cells via HBsAg\/IL-15\/mTOR axis"],"prefix":"10.1038","volume":"16","author":[{"given":"Yating","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ailu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yucan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuiping","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6511-2308","authenticated-orcid":false,"given":"Qiuju","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huajun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5106-1397","authenticated-orcid":false,"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"8069_CR1","doi-asserted-by":"publisher","first-page":"2053","DOI":"10.1016\/S0140-6736(14)60220-8","volume":"384","author":"C Tr\u00e9po","year":"2014","unstructured":"Tr\u00e9po C, Chan HL, Lok A. Hepatitis B virus infection. Lancet. 2014;384:2053\u201363.","journal-title":"Lancet"},{"key":"8069_CR2","unstructured":"European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370\u201398."},{"key":"8069_CR3","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/s41423-020-00561-z","volume":"18","author":"Y Chen","year":"2021","unstructured":"Chen Y, Tian Z. Innate lymphocytes: pathogenesis and therapeutic targets of liver diseases and cancer. Cell Mol Immunol. 2021;18:57\u201372.","journal-title":"Cell Mol Immunol"},{"key":"8069_CR4","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1126\/science.1198687","volume":"331","author":"E Vivier","year":"2011","unstructured":"Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, et al. Innate or adaptive immunity? The example of natural killer cells. Science. 2011;331:44\u201349.","journal-title":"Science"},{"key":"8069_CR5","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.jhep.2010.07.009","volume":"54","author":"ET Tjwa","year":"2011","unstructured":"Tjwa ET, van Oord GW, Hegmans JP, Janssen HL, Woltman AM. Viral load reduction improves activation and function of natural killer cells in patients with chronic hepatitis B. J Hepatol. 2011;54:209\u201318.","journal-title":"J Hepatol"},{"key":"8069_CR6","doi-asserted-by":"publisher","first-page":"e1002594","DOI":"10.1371\/journal.ppat.1002594","volume":"8","author":"C Sun","year":"2012","unstructured":"Sun C, Fu B, Gao Y, Liao X, Sun R, Tian Z, et al. TGF-beta1 down-regulation of NKG2D\/DAP10 and 2B4\/SAP expression on human NK cells contributes to HBV persistence. PLoS Pathog. 2012;8:e1002594.","journal-title":"PLoS Pathog"},{"key":"8069_CR7","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1016\/j.jhep.2009.12.005","volume":"52","author":"Y Ju","year":"2010","unstructured":"Ju Y, Hou N, Meng J, Wang X, Zhang X, Zhao D, et al. T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates natural killer cell suppression in chronic hepatitis B. J Hepatol. 2010;52:322\u20139.","journal-title":"J Hepatol"},{"key":"8069_CR8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1074\/jbc.R115.693903","volume":"291","author":"RM Loftus","year":"2016","unstructured":"Loftus RM, Finlay DK. Immunometabolism: cellular metabolism turns immune regulator. J Biol Chem. 2016;291:1\u201310.","journal-title":"J Biol Chem"},{"key":"8069_CR9","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1038\/ni.3838","volume":"18","author":"N Assmann","year":"2017","unstructured":"Assmann N, O\u2019Brien KL, Donnelly RP, Dyck L, Zaiatz-Bittencourt V, Loftus RM, et al. Srebp-controlled glucose metabolism is essential for NK cell functional responses. Nat Immunol. 2017;18:1197\u2013206.","journal-title":"Nat Immunol"},{"key":"8069_CR10","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.95128","volume":"2","author":"Y Kim","year":"2017","unstructured":"Kim Y, Park SJ, Manson SR, Molina CA, Kidd K, Thiessen-Philbrook H, et al. Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control. JCI Insight. 2017;2:e95128.","journal-title":"JCI Insight"},{"key":"8069_CR11","doi-asserted-by":"publisher","first-page":"1954","DOI":"10.4049\/jimmunol.1402099","volume":"194","author":"MP Keppel","year":"2015","unstructured":"Keppel MP, Saucier N, Mah AY, Vogel TP, Cooper MA. Activation-specific metabolic requirements for NK Cell IFN-gamma production. J Immunol. 2015;194:1954\u201362.","journal-title":"J Immunol"},{"key":"8069_CR12","doi-asserted-by":"publisher","first-page":"2552","DOI":"10.4049\/jimmunol.1501783","volume":"196","author":"SE Keating","year":"2016","unstructured":"Keating SE, Zaiatz-Bittencourt V, Loftus RM, Keane C, Brennan K, Finlay DK, et al. Metabolic reprogramming supports IFN-gamma production by CD56bright NK cells. J Immunol. 2016;196:2552\u201360.","journal-title":"J Immunol"},{"key":"8069_CR13","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1016\/j.cmet.2021.03.023","volume":"33","author":"SM Poznanski","year":"2021","unstructured":"Poznanski SM, Singh K, Ritchie TM, Aguiar JA, Fan IY, Portillo AL, et al. Metabolic flexibility determines human NK cell functional fate in the tumor microenvironment. Cell Metab. 2021;33:1205\u201320.","journal-title":"Cell Metab"},{"key":"8069_CR14","doi-asserted-by":"publisher","first-page":"1656","DOI":"10.1038\/s41590-019-0511-1","volume":"20","author":"X Zheng","year":"2019","unstructured":"Zheng X, Qian Y, Fu B, Jiao D, Jiang Y, Chen P, et al. Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance. Nat Immunol. 2019;20:1656\u201367.","journal-title":"Nat Immunol"},{"key":"8069_CR15","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.173099","volume":"9","author":"E Moreno-Cubero","year":"2024","unstructured":"Moreno-Cubero E, Alrubayyi A, Balint S, Ogbe A, Gill US, Matthews R, et al. IL-15 reprogramming compensates for NK cell mitochondrial dysfunction in HIV-1 infection. JCI Insight. 2024;9:e173099.","journal-title":"JCI Insight"},{"key":"8069_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25715-z","volume":"12","author":"E Littwitz-Salomon","year":"2021","unstructured":"Littwitz-Salomon E, Moreira D, Frost JN, Choi C, Liou KT, Ahern DK, et al. Metabolic requirements of NK cells during the acute response against retroviral infection. Nat Commun. 2021;12:5376.","journal-title":"Nat Commun"},{"key":"8069_CR17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.654225","volume":"12","author":"AUH Khan","year":"2021","unstructured":"Khan AUH, Almutairi SM, Ali AK, Salcedo R, Stewart CA, Wang L, et al. Expression of nutrient transporters on NK cells during murine cytomegalovirus infection is MyD88-dependent. Front Immunol. 2021;12:654225.","journal-title":"Front Immunol"},{"key":"8069_CR18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1064101","volume":"14","author":"KY Osuna-Espinoza","year":"2023","unstructured":"Osuna-Espinoza KY, Rosas-Taraco AG. Metabolism of NK cells during viral infections. Front Immunol. 2023;14:1064101.","journal-title":"Front Immunol"},{"key":"8069_CR19","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1146\/annurev-pharmtox-010611-134537","volume":"52","author":"K Inoki","year":"2012","unstructured":"Inoki K, Kim J, Guan KL. AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharm Toxicol. 2012;52:381\u2013400.","journal-title":"Annu Rev Pharm Toxicol"},{"key":"8069_CR20","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.cotox.2018.05.002","volume":"8","author":"C Garza-Lomb\u00f3","year":"2018","unstructured":"Garza-Lomb\u00f3 C, Schroder A, Reyes-Reyes EM, Franco R. mTOR\/AMPK signaling in the brain: cell metabolism, proteostasis and survival. Curr Opin Toxicol. 2018;8:102\u201310.","journal-title":"Curr Opin Toxicol"},{"key":"8069_CR21","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1186\/s13046-023-02927-3","volume":"42","author":"HJ Yun","year":"2023","unstructured":"Yun HJ, Li M, Guo D, Jeon SM, Park SH, Lim JS, et al. AMPK-HIF-1\u03b1 signaling enhances glucose-derived de novo serine biosynthesis to promote glioblastoma growth. J Exp Clin Cancer Res. 2023;42:340.","journal-title":"J Exp Clin Cancer Res"},{"key":"8069_CR22","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1038\/s41568-018-0074-8","volume":"18","author":"D Mossmann","year":"2018","unstructured":"Mossmann D, Park S, Hall MN. mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat Rev Cancer. 2018;18:744\u201357.","journal-title":"Nat Rev Cancer"},{"key":"8069_CR23","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/nri3901","volume":"15","author":"T Weichhart","year":"2015","unstructured":"Weichhart T, Hengstschl\u00e4ger M, Linke M. Regulation of innate immune cell function by mTOR. Nat Rev Immunol. 2015;15:599\u2013614.","journal-title":"Nat Rev Immunol"},{"key":"8069_CR24","doi-asserted-by":"publisher","first-page":"2278","DOI":"10.3390\/cells9102278","volume":"9","author":"S Huang","year":"2020","unstructured":"Huang S. mTOR signaling in metabolism and cancer. Cells. 2020;9:2278.","journal-title":"Cells"},{"key":"8069_CR25","doi-asserted-by":"publisher","first-page":"3315","DOI":"10.4161\/15384101.2014.972919","volume":"13","author":"A Mar\u00e7ais","year":"2014","unstructured":"Mar\u00e7ais A, Walzer T. mTOR: a gate to NK cell maturation and activation. Cell Cycle. 2014;13:3315\u20136.","journal-title":"Cell Cycle"},{"key":"8069_CR26","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1038\/ni.2936","volume":"15","author":"A Mar\u00e7ais","year":"2014","unstructured":"Mar\u00e7ais A, Cherfils-Vicini J, Viant C, Degouve S, Viel S, Fenis A, et al. The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat Immunol. 2014;15:749\u201357.","journal-title":"Nat Immunol"},{"key":"8069_CR27","doi-asserted-by":"publisher","first-page":"1475","DOI":"10.1182\/blood-2016-02-698027","volume":"128","author":"Y Mao","year":"2016","unstructured":"Mao Y, van Hoef V, Zhang X, Wennerberg E, Lorent J, Witt K, et al. IL-15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells. Blood. 2016;128:1475\u201389.","journal-title":"Blood"},{"key":"8069_CR28","doi-asserted-by":"publisher","first-page":"95","DOI":"10.7554\/eLife.60095","volume":"10","author":"M Marotel","year":"2021","unstructured":"Marotel M, Villard M, Drouillard A, Tout I, Besson L, Allatif O, et al. Peripheral natural killer cells in chronic hepatitis B patients display multiple molecular features of T cell exhaustion. Elife. 2021;10:95\u2013117.","journal-title":"Elife"},{"key":"8069_CR29","doi-asserted-by":"publisher","first-page":"4477","DOI":"10.4049\/jimmunol.1401558","volume":"193","author":"RP Donnelly","year":"2014","unstructured":"Donnelly RP, Loftus RM, Keating SE, Liou KT, Biron CA, Gardiner CM, et al. mTORC1-dependent metabolic reprogramming is a prerequisite for NK cell effector function. J Immunol. 2014;193:4477\u201384.","journal-title":"J Immunol"},{"key":"8069_CR30","doi-asserted-by":"publisher","first-page":"2032","DOI":"10.1136\/gutjnl-2017-315588","volume":"68","author":"HJ Zhao","year":"2019","unstructured":"Zhao HJ, Han QJ, Wang G, Lin A, Xu DQ, Wang YQ, et al. Poly I:C-based rHBVvac therapeutic vaccine eliminates HBV via generation of HBV-specific CD8+ effector memory T cells. Gut. 2019;68:2032\u201343.","journal-title":"Gut"},{"key":"8069_CR31","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1053\/j.gastro.2008.07.008","volume":"135","author":"MF Yuen","year":"2008","unstructured":"Yuen MF, Wong DK, Fung J, Ip P, But D, Hung I, et al. HBsAg seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology. 2008;135:1192\u20139.","journal-title":"Gastroenterology"},{"key":"8069_CR32","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1002\/JLB.2A1118-421R","volume":"106","author":"B Zheng","year":"2019","unstructured":"Zheng B, Yang Y, Han Q, Yin C, Pan Z, Zhang J. STAT3 directly regulates NKp46 transcription in NK cells of HBeAg-negative CHB patients. J Leukoc Biol. 2019;106:987\u201396.","journal-title":"J Leukoc Biol"},{"key":"8069_CR33","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.cytogfr.2016.06.001","volume":"31","author":"M Patidar","year":"2016","unstructured":"Patidar M, Yadav N, Dalai SK. Interleukin 15: a key cytokine for immunotherapy. Cytokine Growth Factor Rev. 2016;31:49\u201359.","journal-title":"Cytokine Growth Factor Rev"},{"key":"8069_CR34","doi-asserted-by":"publisher","first-page":"4122","DOI":"10.4049\/jimmunol.1500846","volume":"196","author":"M Zheng","year":"2016","unstructured":"Zheng M, Sun R, Wei H, Tian Z. NK cells help induce anti-hepatitis B virus CD8+ T cell immunity in mice. J Immunol. 2016;196:4122\u201331.","journal-title":"J Immunol"},{"key":"8069_CR35","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1182\/blood.2021011532","volume":"139","author":"MM Berrien-Elliott","year":"2022","unstructured":"Berrien-Elliott MM, Becker-Hapak M, Cashen AF, Jacobs M, Wong P, Foster M, et al. Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy. Blood. 2022;139:1177\u201383.","journal-title":"Blood"},{"key":"8069_CR36","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1038\/s41577-021-00558-3","volume":"22","author":"NK Bj\u00f6rkstr\u00f6m","year":"2022","unstructured":"Bj\u00f6rkstr\u00f6m NK, Strunz B, Ljunggren HG. Natural killer cells in antiviral immunity. Nat Rev Immunol. 2022;22:112\u201323.","journal-title":"Nat Rev Immunol"},{"key":"8069_CR37","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1053\/j.gastro.2012.10.039","volume":"144","author":"F Li","year":"2013","unstructured":"Li F, Wei H, Wei H, Gao Y, Xu L, Yin W, et al. Blocking the natural killer cell inhibitory receptor NKG2A increases activity of human natural killer cells and clears hepatitis B virus infection in mice. Gastroenterology. 2013;144:392\u2013401.","journal-title":"Gastroenterology"},{"key":"8069_CR38","doi-asserted-by":"publisher","first-page":"2673","DOI":"10.1080\/2162402X.2021.1942673","volume":"10","author":"L Yu","year":"2021","unstructured":"Yu L, Liu X, Wang X, Yan F, Wang P, Jiang Y, et al. TIGIT+ TIM-3+ NK cells are correlated with NK cell exhaustion and disease progression in patients with hepatitis B virus\u2011related hepatocellular carcinoma. Oncoimmunology. 2021;10:2673\u201386.","journal-title":"Oncoimmunology"},{"key":"8069_CR39","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.3389\/fimmu.2018.01124","volume":"9","author":"D Zhao","year":"2018","unstructured":"Zhao D, Jiang X, Xu Y, Yang H, Gao D, Li X, et al. Decreased siglec-9 expression on natural killer cell subset associated with persistent HBV replication. Front Immunol. 2018;9:1124.","journal-title":"Front Immunol"},{"key":"8069_CR40","doi-asserted-by":"publisher","first-page":"1900","DOI":"10.1038\/s41418-020-00715-6","volume":"28","author":"D Li","year":"2021","unstructured":"Li D, Wang Y, Yang M, Dong Z. mTORC1 and mTORC2 coordinate early NK cell development by differentially inducing E4BP4 and T-bet. Cell Death Differ. 2021;28:1900\u20139.","journal-title":"Cell Death Differ"},{"key":"8069_CR41","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07277-9","volume":"9","author":"F Wang","year":"2018","unstructured":"Wang F, Meng M, Mo B, Yang Y, Ji Y, Huang P, et al. Crosstalks between mTORC1 and mTORC2 variagate cytokine signaling to control NK maturation and effector function. Nat Commun. 2018;9:4874.","journal-title":"Nat Commun"},{"key":"8069_CR42","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1136\/jitc-2020-001428","volume":"8","author":"PF Fiore","year":"2020","unstructured":"Fiore PF, Di Matteo S, Tumino N, Mariotti FR, Pietra G, Ottonello S, et al. Interleukin-15 and cancer: some solved and many unsolved questions. J Immunother Cancer. 2020;8:428\u201339.","journal-title":"J Immunother Cancer"},{"key":"8069_CR43","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1111\/j.1478-3231.2012.02773.x","volume":"32","author":"W Yin","year":"2012","unstructured":"Yin W, Xu L, Sun R, Wei H, Tian Z. Interleukin-15 suppresses hepatitis B virus replication via IFN-beta production in a C57BL\/6 mouse model. Liver Int. 2012;32:1306\u201314.","journal-title":"Liver Int"},{"key":"8069_CR44","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1007\/s12072-017-9803-4","volume":"11","author":"T Chen","year":"2017","unstructured":"Chen T, Zhu L, Shi A, Ding L, Zhang X, Tan Z, et al. Functional restoration of CD56bright NK cells facilitates immune control via IL-15 and NKG2D in patients under antiviral treatment for chronic hepatitis B. Hepatol Int. 2017;11:419\u201328.","journal-title":"Hepatol Int"},{"key":"8069_CR45","doi-asserted-by":"publisher","first-page":"2087","DOI":"10.1016\/j.molimm.2011.07.008","volume":"48","author":"ML Hansen","year":"2011","unstructured":"Hansen ML, Woetmann A, Krejsgaard T, Kopp KL, S\u00f8kilde R, Litman T, et al. IFN-alpha primes T- and NK-cells for IL-15-mediated signaling and cytotoxicity. Mol Immunol. 2011;48:2087\u201393.","journal-title":"Mol Immunol"},{"key":"8069_CR46","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/j.intimp.2016.06.015","volume":"38","author":"Y Yang","year":"2016","unstructured":"Yang Y, Han Q, Zhang C, Xiao M, Zhang J. Hepatitis B virus antigens impair NK cell function. Int Immunopharmacol. 2016;38:291\u20137.","journal-title":"Int Immunopharmacol"},{"key":"8069_CR47","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.coi.2016.10.004","volume":"44","author":"J Rautela","year":"2017","unstructured":"Rautela J, Huntington ND. IL-15 signaling in NK cell cancer immunotherapy. Curr Opin Immunol. 2017;44:1\u20136.","journal-title":"Curr Opin Immunol"},{"key":"8069_CR48","doi-asserted-by":"publisher","first-page":"1280","DOI":"10.1016\/j.cell.2020.02.029","volume":"180","author":"A Crinier","year":"2020","unstructured":"Crinier A, Narni-Mancinelli E, Ugolini S, Vivier E. Snapshot: natural killer cells. Cell. 2020;180:1280\u20131280.e1.","journal-title":"Cell"},{"key":"8069_CR49","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.lfs.2018.01.001","volume":"195","author":"W Han","year":"2018","unstructured":"Han W, Ni Q, Liu K, Yao Y, Zhao D, Liu X, et al. Decreased CD122 on CD56dim NK associated with its impairment in asymptomatic chronic HBV carriers with high levels of HBV DNA, HBsAg and HBeAg. Life Sci. 2018;195:53\u201360.","journal-title":"Life Sci"},{"key":"8069_CR50","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1016\/j.it.2022.08.004","volume":"43","author":"S Ma","year":"2022","unstructured":"Ma S, Caligiuri MA, Yu J. Harnessing IL-15 signaling to potentiate NK cell-mediated cancer immunotherapy. Trends Immunol. 2022;43:833\u201347.","journal-title":"Trends Immunol"},{"key":"8069_CR51","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.stem.2020.05.008","volume":"27","author":"H Zhu","year":"2020","unstructured":"Zhu H, Blum RH, Bernareggi D, Ask EH, Wu Z, Hoel HJ, et al. Metabolic reprograming via deletion of CISH in human iPSC-derived NK cells promotes in vivo persistence and enhances anti-tumor activity. Cell Stem Cell. 2020;27:224\u2013.e6.","journal-title":"Cell Stem Cell"},{"key":"8069_CR52","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1038\/ni.3470","volume":"17","author":"RB Delconte","year":"2016","unstructured":"Delconte RB, Kolesnik TB, Dagley LF, Rautela J, Shi W, Putz EM, et al. CIS is a potent checkpoint in NK cell-mediated tumor immunity. Nat Immunol. 2016;17:816\u201324.","journal-title":"Nat Immunol"},{"key":"8069_CR53","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20200298","volume":"217","author":"V Fumagalli","year":"2020","unstructured":"Fumagalli V, Di Lucia P, Venzin V, Bono EB, Jordan R, Frey CR, et al. Serum HBsAg clearance has minimal impact on CD8+ T cell responses in mouse models of HBV infection. J Exp Med. 2020;217:e20200298.","journal-title":"J Exp Med"},{"key":"8069_CR54","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.ijid.2016.03.024","volume":"46","author":"S Lan","year":"2016","unstructured":"Lan S, Wu L, Wang X, Wu J, Lin X, Wu W, et al. Impact of HBeAg on the maturation and function of dendritic cells. Int J Infect Dis. 2016;46:42\u201348.","journal-title":"Int J Infect Dis"},{"key":"8069_CR55","doi-asserted-by":"publisher","first-page":"2640","DOI":"10.1016\/j.molimm.2009.04.031","volume":"46","author":"Y Xu","year":"2009","unstructured":"Xu Y, Hu Y, Shi B, Zhang X, Wang J, Zhang Z, et al. HBsAg inhibits TLR9-mediated activation and IFN-alpha production in plasmacytoid dendritic cells. Mol Immunol. 2009;46:2640\u20136.","journal-title":"Mol Immunol"},{"key":"8069_CR56","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1038\/s41423-022-00939-1","volume":"19","author":"H Zhao","year":"2022","unstructured":"Zhao H, Yu Y, Wang Y, Zhao L, Yang A, Hu Y, et al. Cholesterol accumulation on dendritic cells reverses chronic hepatitis B virus infection-induced dysfunction. Cell Mol Immunol. 2022;19:1347\u201360.","journal-title":"Cell Mol Immunol"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08069-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08069-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08069-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T08:02:32Z","timestamp":1760342552000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08069-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,13]]},"references-count":56,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["8069"],"URL":"https:\/\/doi.org\/10.1038\/s41419-025-08069-y","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,13]]},"assertion":[{"value":"3 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 August 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 September 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 October 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All animal experiments were performed in accordance with the Guidelines for the Care and Use of Laboratory Animals and the Ethical Committee of Shandong University and using protocols approved by the Institutional Animal Care and Use Committee of Shandong University (approval number: 230018). The human study was approved by the guidelines of the Ethics Committee of Shandong University (approval number: KYLL-2023-278). All procedures were performed in accordance with the Declaration of Helsinki. Informed consent was obtained from all participants for the use of samples and clinical data in experiments and for publication.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"721"}}