{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T19:23:51Z","timestamp":1793301831464,"version":"4.5.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    In chronic hepatitis B virus infection (cHBV), T-cell responses are skewed. This prevents the elimination of HBV-infected hepatocytes, contributes to hepatocellular carcinoma development, and limits the efficacy of T-cell therapies. To counteract the immune checkpoint PD-1\/PD-L1\u2013interaction in adoptive T-cell therapy, we developed PD-1\u2013based immunoswitch receptors that convert PD-L1 engagement into co-stimulation. We designed immunoswitch receptors linking a PD-1 ectodomain to intracellular CD28, 4-1BB, or OX40 signaling domains and expressed them in HBV-specific chimeric antigen receptor (CAR)- and T-cell receptor-engineered T cells. T-cell activity was assessed in antigen- and PD-L1-dependent co-cultures, transcription factor reporter systems, and an HBV carrier mouse model. Second-generation S-CAR functionality was not improved by signal stacking of additional co-stimulatory domains, resulting in a dysfunctional activation state rather than an additive benefit. In contrast, modular delivery of co-stimulation through PD-1-based immunoswitch receptors enhanced antigen sensitivity, functionality, and cytotoxicity of engineered T cells. PD-L1 supplied in trans was sufficient to support on-target functionality of engineered T cells by immunoswitch receptor co-stimulation. PD-1_4-1BB proved superior at inducing sustained NF-\u03baB signaling and reducing exhaustion-associated pathways.\n                    <jats:italic>In vivo<\/jats:italic>\n                    , PD-1_4-1BB improved T-cell persistence and decreased TOX upregulation. PD-1\u2013based immunoswitch receptors offer a modular strategy to strengthen engineered T-cell responses against HBV antigen-expressing cells in the liver\u2019s tolerizing environment. This ligand-driven approach enables precise tuning of co-stimulation, generating a versatile platform for enhancing adoptive T-cell therapies in chronic infections and cancer.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1821414","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T05:39:57Z","timestamp":1783057197000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Modular delivery of co-stimulatory signals through a PD-1-based immunoswitch receptor improves the functionality of Hepatitis B Virus-specific engineered T cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Luis Felipe","family":"Olgu\u00edn-Contreras","sequence":"first","affiliation":[{"name":"Institute of Virology, Technical University of Munich, School of Medicine and Health","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Heep","sequence":"additional","affiliation":[{"name":"Institute of Virology, Technical University of Munich, School of Medicine and Health","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Schiller","sequence":"additional","affiliation":[{"name":"Institute of Virology, Technical University of Munich, School of Medicine and Health","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Loffredo-Verde","sequence":"additional","affiliation":[{"name":"Institute of Virology, Technical University of Munich, School of Medicine and Health","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin M.","family":"Festag","sequence":"additional","affiliation":[{"name":"Institute of Virology, Technical University of Munich, School of Medicine and Health","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Metzger","sequence":"additional","affiliation":[{"name":"Institute of Virology, Technical University of Munich, School of Medicine and Health","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"F\u00e4rber","sequence":"additional","affiliation":[{"name":"Institute of Virology, Technical University of Munich, School of Medicine and Health","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merve","family":"G\u00fcltan","sequence":"additional","affiliation":[{"name":"Institute of Virology, Technical University of Munich, School of Medicine and Health","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Tulessin","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Technical University of Munich, School of Medicine and Health","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Wilde","sequence":"additional","affiliation":[{"name":"SCG Cell Therapy GmbH","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Wisskirchen","sequence":"additional","affiliation":[{"name":"Institute of Virology, Technical University of Munich, School of Medicine and Health","place":["Munich, Germany"]},{"name":"SCG Cell Therapy GmbH","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elfriede","family":"Noessner","sequence":"additional","affiliation":[{"name":"Immunanalytics-Tissue Control of Immunocytes, Helmholtz Center Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Protzer","sequence":"additional","affiliation":[{"name":"Institute of Virology, Technical University of Munich, School of Medicine and Health","place":["Munich, Germany"]},{"name":"Institute of Virology, Helmholtz Center Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"B1","unstructured":"Global Hepatitis Report 2024\n          \n          \n          \n          2024"},{"key":"B2","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/S2468-1253(18)30056-6","article-title":"Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study","volume":"3","author":"Razavi-Shearer","year":"2018","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.1053\/j.gastro.2011.12.061","article-title":"Epidemiology of viral hepatitis and hepatocellular carcinoma","volume":"142","author":"El-Serag","year":"2012","journal-title":"Gastroenterology"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2016.06.003","article-title":"HBV cure: why, how, when","volume":"18","author":"Levrero","year":"2016","journal-title":"Curr Opin Virol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/v9060156","article-title":"The role of cccDNA in HBV maintenance","volume":"9","author":"Allweiss","year":"2017","journal-title":"Viruses"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.08.061","article-title":"Insights from antiviral therapy into immune responses to hepatitis B and C virus infection","volume":"156","author":"Rehermann","year":"2019","journal-title":"Gastroenterology"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nri3862","article-title":"Molecular and cellular insights into T cell exhaustion","volume":"15","author":"Wherry","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1053\/j.gastro.2012.07.014","article-title":"Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues","volume":"143","author":"Boni","year":"2012","journal-title":"Gastroenterology"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0047648","article-title":"Upregulation of the Tim-3\/Galectin-9 pathway of T cell exhaustion in chronic hepatitis B virus infection","volume":"7","author":"Nebbia","year":"2012","journal-title":"PloS One"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.25397","article-title":"PD-1 and PD-L1 upregulation promotes CD8+ T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients","volume":"128","author":"Shi","year":"2011","journal-title":"Int J Cancer"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.192461099","article-title":"Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade","volume":"99","author":"Iwai","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2016.5","article-title":"Immunological functions of liver sinusoidal endothelial cells","volume":"13","author":"Knolle","year":"2016","journal-title":"Cell Mol Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2010.10.025","article-title":"Engineering virus-specific T cells that target HBV infected hepatocytes and hepatocellular carcinoma cell lines","volume":"55","author":"Gehring","year":"2011","journal-title":"J Hepatol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.11.002","article-title":"T cells redirected against hepatitis B virus surface proteins eliminate infected hepatocytes","volume":"134","author":"Bohne","year":"2008","journal-title":"Gastroenterology"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1172\/JCI93024","article-title":"Lymphocytes transiently expressing virus-specific T cell receptors reduce hepatitis B virus infection","volume":"127","author":"Kah","year":"2017","journal-title":"J Clin Invest"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1172\/JCI120228","article-title":"T cell receptor grafting allows virological control of hepatitis B virus infection","volume":"129","author":"Wisskirchen","year":"2019","journal-title":"J Clin Invest"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2019.02.001","article-title":"Evaluation of a fully human, hepatitis B virus-specific chimeric antigen receptor in an immunocompetent mouse model","volume":"27","author":"Festag","year":"2019","journal-title":"Mol Ther"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1340619","article-title":"CARs derived from broadly neutralizing, human monoclonal antibodies identified by single B cell sorting target hepatitis B virus-positive cells","volume":"15","author":"Schreiber","year":"2024","journal-title":"Front Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3350\/CMH.2024.0469","article-title":"Engineering HBV-specific T cells for the treatment of HBV-related HCC and HBV infection: Past, present, and future. Editorial on \u201cGenetically-modified, redirected T cells target hepatitis B surface antigen-positive hepatocytes and hepatocellular carcinoma","volume":"30","author":"Bertoletti","year":"2024","journal-title":"Clin Mol Hepatol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2025.102004","article-title":"HBV antigen as a tumour antigen in adoptive TCR-T cell therapy for HBV-related HCC: rationale and clinical effectiveness","volume":"80","author":"He","year":"2025","journal-title":"Semin Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2025-335456","article-title":"Clinical results of an HBV-specific T-cell receptor-T-cell therapy (SCG101) in patients with HBV-related hepatocellular carcinoma treated in an investigator-initiated, interventional trial","volume":"75","author":"Wu","year":"2026","journal-title":"Gut"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2025.06.007","article-title":"Chimeric antigen receptor (CAR) T-cell therapy: Engineering immune cells to treat liver diseases","volume":"83","author":"Jaeckel","year":"2025","journal-title":"J Hepatol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003208","article-title":"The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells","volume":"9","author":"Schurich","year":"2013","journal-title":"PloS Pathog"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.064","article-title":"Antigen-specific activation and cytokine-facilitated expansion of naive, human CD8+ T cells","volume":"9","author":"W\u00f6lfl","year":"2014","journal-title":"Nat Protoc"},{"key":"B25","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.immuni.2013.07.002","article-title":"Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology","volume":"39","author":"Kalos","year":"2013","journal-title":"Immunity"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3838","article-title":"4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors","volume":"21","author":"Long","year":"2015","journal-title":"Nat Med"},{"key":"B27","doi-asserted-by":"publisher","first-page":"4078","DOI":"10.1016\/j.cell.2024.05.038","article-title":"Therapeutic potential of co-signaling receptor modulation in hepatitis B","volume":"187","author":"Andreata","year":"2024","journal-title":"Cell"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2013.43","article-title":"A practical approach to immunotherapy of hepatocellular carcinoma using T cells redirected against hepatitis B virus","volume":"2","author":"Koh","year":"2013","journal-title":"Mol Ther Nucleic Acids"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2012.03.023","article-title":"Tumor PD-L1 co-stimulates primary human CD8+ cytotoxic T cells modified to express a PD1: CD28 chimeric receptor","volume":"51","author":"Prosser","year":"2012","journal-title":"Mol Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-2524","article-title":"A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors","volume":"76","author":"Liu","year":"2016","journal-title":"Cancer Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-1922","article-title":"Chimeric PD-1:28 receptor upgrades low-avidity T cells and restores effector function of tumor-infiltrating lymphocytes for adoptive cell therapy","volume":"77","author":"Schlenker","year":"2017","journal-title":"Cancer Res"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14081998","article-title":"T-cells expressing a highly potent PRAME-specific T-cell receptor in combination with a chimeric PD1-41BB co-stimulatory receptor show a favorable preclinical safety profile and strong anti-tumor reactivity","volume":"14","author":"Sailer","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.04.047","article-title":"T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice","volume":"145","author":"Krebs","year":"2013","journal-title":"Gastroenterology"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0182936","article-title":"Isolation and functional characterization of hepatitis B virus-specific T-cell receptors as new tools for experimental and clinical use","volume":"12","author":"Wisskirchen","year":"2017","journal-title":"PloS One"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.24807","article-title":"A Jurkat 76 based triple parameter reporter system to evaluate TCR functions and adoptive T cell strategies","volume":"9","author":"Rosskopf","year":"2018","journal-title":"Oncotarget"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1762","DOI":"10.1053\/j.gastro.2020.01.032","article-title":"Knockdown of virus antigen expression increases therapeutic vaccine efficacy in high-titer hepatitis B virus carrier mice","volume":"158","author":"Michler","year":"2020","journal-title":"Gastroenterology"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/vaccines9080841","article-title":"Immunogenicity and antiviral response of therapeutic hepatitis B vaccination in a mouse model of HBeAg-negative, persistent HBV infection","volume":"9","author":"Kosinska","year":"2021","journal-title":"Vaccines"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-02-337360","article-title":"A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells","volume":"118","author":"Wang","year":"2011","journal-title":"Blood"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28710","article-title":"Programmed death ligand 1 expression in hepatocellular carcinoma: Relationship with clinical and pathological features","volume":"64","author":"Calderaro","year":"2016","journal-title":"Hepatology"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.09.004","article-title":"Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells","volume":"28","author":"Zhao","year":"2015","journal-title":"Cancer Cell"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2035","article-title":"T cell exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aau6905","article-title":"Multifactorial heterogeneity of virus-specific T cells and association with the progression of human chronic hepatitis B infection","volume":"4","author":"Cheng","year":"2019","journal-title":"Sci Immunol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.it.2013.10.001","article-title":"Tolerance and exhaustion: Defining mechanisms of T cell dysfunction","volume":"35","author":"Schietinger","year":"2014","journal-title":"Trends Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20171068","article-title":"4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses","volume":"215","author":"Menk","year":"2018","journal-title":"J Exp Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1325-x","article-title":"TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion","volume":"571","author":"Khan","year":"2019","journal-title":"Nature"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/scisignal.aay8248","article-title":"4-1BB costimulation promotes CAR T cell survival through noncanonical NF-\u03baB signaling","volume":"13","author":"Philipson","year":"2020","journal-title":"Sci Signal"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2019.08.010","article-title":"Therapeutic strategies for the costimulatory molecule OX40 in T-cell-mediated immunity","volume":"10","author":"Fu","year":"2020","journal-title":"Acta Pharm Sin B"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.omton.2024.200837","article-title":"Co-stimulation of CD28\/CD40 signaling molecule potentiates CAR-T cell efficacy and stemness","volume":"32","author":"Khopanlert","year":"2024","journal-title":"Mol Ther Oncol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-19-0908","article-title":"Excessive costimulation leads to dysfunction of adoptively transferred T cells","volume":"8","author":"Wijewarnasuriya","year":"2020","journal-title":"Cancer Immunol Res"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.07.009","article-title":"The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction","volume":"45","author":"Scharping","year":"2016","journal-title":"Immunity"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adg0878","article-title":"Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1+ PD-1+ CD8 T cells","volume":"8","author":"Humblin","year":"2023","journal-title":"Sci Immunol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2015.02.008","article-title":"Overcoming T cell exhaustion in infection and cancer","volume":"36","author":"Pauken","year":"2015","journal-title":"Trends Immunol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf2807","article-title":"Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade","volume":"354","author":"Pauken","year":"2016","journal-title":"Science (80-)"},{"key":"B54","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1002\/hep.21965","article-title":"Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance","volume":"47","author":"Diehl","year":"2008","journal-title":"Hepatology"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2019.00015","article-title":"Observational study of PD-L1, TGF-\u03b2, and immune cell infiltrates in hepatocellular carcinoma","volume":"6","author":"Ihling","year":"2019","journal-title":"Front Med"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf1292","article-title":"T cell costimulatory receptor CD28 is a primary target for PD-1\u2013mediated inhibition","volume":"355","author":"Hui","year":"2017","journal-title":"Science (80-)"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2016.01.026","article-title":"Adaptive immunity in HBV infection","volume":"64","author":"Bertoletti","year":"2016","journal-title":"J Hepatol"},{"key":"B58","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1084\/jem.20191663","article-title":"Challenges of CAR- And TCR-T cell-based therapy for chronic infections","volume":"217","author":"Bertoletti","year":"2020","journal-title":"J Exp Med"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07630-7","article-title":"A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection","volume":"631","author":"Bosch","year":"2024","journal-title":"Nature"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1821414\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T05:40:06Z","timestamp":1783057206000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1821414\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,3]]},"references-count":59,"alternative-id":["10.3389\/fimmu.2026.1821414"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1821414","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,3]]},"article-number":"1821414"}}