{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T06:08:22Z","timestamp":1788761302097,"version":"build-2803163510"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"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>Chronic lymphocytic leukemia (CLL) predominantly affects older adults; however, approximately 10% of patients are diagnosed at a younger age. Although overall survival appears comparable across age groups, emerging evidence suggests that early-onset CLL may represent a biologically distinct disease subset. Given the profound effects of aging on immune competence and tumor-host interactions, we investigated whether age at diagnosis influences leukemic cell behavior, microenvironmental responsiveness, and immune dysfunction in CLL. We first analyzed the clinical impact of age at diagnosis in a Uruguayan cohort of 462 CLL patients and subsequently explored the biological basis underlying age-associated differences. Patients were stratified according to age at diagnosis, and disease progression was assessed by time-to-first treatment (TTFT). Metabolic analysis evaluated leukemic cell responses to prototypical tumor microenvironment (TME) stimuli, including CD40L plus IL-4 and CpG-ODN plus IL-15. In parallel, we characterized proliferative and quiescent leukemic fractions in peripheral blood, assessed T-cell exhaustion profiles, and analyzed metabolic reprogramming following microenvironmental stimulation. Patients diagnosed at \u226455 years of age exhibited the shortest TTFT (median 39 months), whereas those aged \u226565 years showed a significantly longer TTFT (median 97,6) confirming the more aggressive clinical course of early-onset CLL, despite the longer overall survival as previously described. Metabolic studies revealed that leukemic cells from younger patients displayed enhanced responsiveness to TME-derived signals, characterized by increased metabolic fitness and greater metabolic reprogramming following stimulation. Moreover, early-onset CLL was enriched in proliferative leukemic fractions, whereas the frequency and distribution of exhausted T-cell subsets were comparable between age groups. Collectively, our findings indicate that age-dependent differences in CLL behavior are primarily associated with intrinsic leukemic cell properties rather than major alterations in T-cell dysfunction. Early-onset CLL is characterized by enhanced metabolic adaptability and enrichment of proliferative leukemic cells, supporting the concept that it constitutes a biologically distinct subset of the disease. Despite the absence of differences in survival between age groups, our results provide new insights into CLL heterogeneity and suggest that age-related differences in leukemic cell\u2013microenvironment interactions may contribute to the more aggressive clinical behavior observed in younger patients.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1936737","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T05:34:33Z","timestamp":1788759273000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Early-onset CLL is characterized by enhanced microenvironment-driven metabolic fitness, increased proliferative bias, and accelerated disease progression"],"prefix":"10.3389","volume":"17","author":[{"given":"Eugenia","family":"Payque","sequence":"first","affiliation":[{"name":"Research Laboratory on Chronic Lymphocytic Leukemia, Institut Pasteur de Montevideo","place":["Montevideo, Uruguay"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago A.","family":"Rodr\u00edguez-Zraquia","sequence":"additional","affiliation":[{"name":"Research Laboratory on Chronic Lymphocytic Leukemia, Institut Pasteur de Montevideo","place":["Montevideo, Uruguay"]},{"name":"Immunobiology Academic Unit, School of Medicine, University of the Republic","place":["Montevideo, Uruguay"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianela","family":"Lasagna","sequence":"additional","affiliation":[{"name":"Research Laboratory on Chronic Lymphocytic Leukemia, Institut Pasteur de Montevideo","place":["Montevideo, Uruguay"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Uria","sequence":"additional","affiliation":[{"name":"Research Laboratory on Chronic Lymphocytic Leukemia, Institut Pasteur de Montevideo","place":["Montevideo, Uruguay"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanesa A.","family":"Guazzone","sequence":"additional","affiliation":[{"name":"Research Laboratory on Chronic Lymphocytic Leukemia, Institut Pasteur de Montevideo","place":["Montevideo, Uruguay"]},{"name":"Facultad de Medicina, Departamento de Histolog\u00eda, Embriolog\u00eda, Biolog\u00eda Celular y Gen\u00e9tica, Universidad de Buenos Aires","place":["Buenos Aires, Argentina"]},{"name":"Instituto de Investigaciones Biom\u00e9dicas (INBIOMED), CONICET- Universidad de Buenos Aires","place":["Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Irigoin","sequence":"additional","affiliation":[{"name":"Hematology Department, Centro de Asistencia del Sindicato M\u00e9dico del Uruguay (CASMU)","place":["Montevideo, Uruguay"]},{"name":"Hematology Department, Instituci\u00f3n de Asistencia M\u00e9dica Privada de Profesionales (COSEM)","place":["Montevideo, Uruguay"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana In\u00e9s","family":"Landoni","sequence":"additional","affiliation":[{"name":"Hospital Maciel, ASSE","place":["Montevideo, Uruguay"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Remedi","sequence":"additional","affiliation":[{"name":"Hospital Maciel, ASSE","place":["Montevideo, Uruguay"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Lema","sequence":"additional","affiliation":[{"name":"Hematology Department, Direcci\u00f3n Nacional de Sanidad de las Fuerzas Armadas","place":["Montevideo, Uruguay"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Ranero","sequence":"additional","affiliation":[{"name":"Unidad Acad\u00e9mica de Hematolog\u00eda. Hospital de Cl\u00ednicas, Facultad de Medicina, Universidad de la Rep\u00fablica","place":["Montevideo, Uruguay"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"de Galvez","sequence":"additional","affiliation":[{"name":"Hematology Department, Centro de Asistencia del Sindicato M\u00e9dico del Uruguay (CASMU)","place":["Montevideo, Uruguay"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ra\u00fal","family":"Gabus","sequence":"additional","affiliation":[{"name":"Hospital Maciel, ASSE","place":["Montevideo, Uruguay"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Muxi","sequence":"additional","affiliation":[{"name":"Hematology Department, Hospital Brit\u00e1nico","place":["Montevideo, Uruguay"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helga","family":"Simon-Molas","sequence":"additional","affiliation":[{"name":"Amsterdam University Medical Centers (UMC) location University of Amsterdam, Experimental Immunology, and location Vrije Universiteit Amsterdam, Hematology","place":["Amsterdam, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Oliver","sequence":"additional","affiliation":[{"name":"Hematology Department, Centro de Asistencia del Sindicato M\u00e9dico del Uruguay (CASMU)","place":["Montevideo, Uruguay"]},{"name":"Hematology Department, Hospital Brit\u00e1nico","place":["Montevideo, Uruguay"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Oppezzo","sequence":"additional","affiliation":[{"name":"Research Laboratory on Chronic Lymphocytic Leukemia, Institut Pasteur de Montevideo","place":["Montevideo, Uruguay"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.27546","article-title":"Chronic lymphocytic leukemia: 2025 update on the epidemiology, pathogenesis, diagnosis, and therapy","volume":"100","author":"Hallek","year":"2025","journal-title":"Am J Hematol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1200\/EDBK-25-473656","article-title":"When and how long to treat chronic lymphocytic leukemia","volume":"45","author":"Niemann","year":"2025","journal-title":"Am Soc Clin Oncol Educ Book"},{"key":"B3","doi-asserted-by":"publisher","first-page":"16096","DOI":"10.1038\/nrdp.2016.96","article-title":"Chronic lymphocytic leukaemia","volume":"3","author":"Kipps","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.21.120601.141018","article-title":"B cell chronic lymphocytic leukemia: Lessons learned from studies of the B cell antigen receptor","volume":"21","author":"Chiorazzi","year":"2003","journal-title":"Annu Rev Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1172\/JCI23409","article-title":"In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells","volume":"115","author":"Messmer","year":"2005","journal-title":"J Clin Invest"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2011.00360","article-title":"Intraclonal complexity in chronic lymphocytic leukemia: fractions enriched in recently born\/divided and older\/quiescent cells","volume":"17","author":"Calissano","year":"2011","journal-title":"Mol Med"},{"key":"B7","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/leu.2013.248","article-title":"Clonal evolution in hematological Malignancies and therapeutic implications","volume":"28","author":"Landau","year":"2014","journal-title":"Leukemia"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2014.158","article-title":"Activation of the PI3K\/AKT pathway by microRNA-22 results in CLL B-cell proliferation","volume":"29","author":"Palacios","year":"2015","journal-title":"Leukemia"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1002\/hem3.70064","article-title":"Proliferating CLL cells express high levels of CXCR4 and CD5","volume":"8","author":"Friedman","year":"2024","journal-title":"Hemasphere"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-12-257758","article-title":"High expression of AID and active class switch recombination might account for a more aggressive disease in unmutated CLL patients: link with an activated microenvironment in CLL disease","volume":"115","author":"Palacios","year":"2010","journal-title":"Blood"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1097\/HS9.0000000000000722","article-title":"B-cell receptor signaling induced metabolic alterations in chronic lymphocytic leukemia can be partially bypassed by TP53 abnormalities","volume":"6","author":"Kluckova","year":"2022","journal-title":"Hemasphere"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminhematol.2024.02.001","article-title":"Metabolic reprogramming in the CLL TME; potential for new therapeutic targets","volume":"61","author":"Simon-Molas","year":"2024","journal-title":"Semin Hematol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-09-457531","article-title":"T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production","volume":"121","author":"Riches","year":"2013","journal-title":"Blood"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.70180","article-title":"Integrative perspectives on signaling, mechanics, and immune interactions in B-cell Malignancies","volume":"599","author":"Perez-Galan","year":"2025","journal-title":"FEBS Lett"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminhematol.2014.05.006","article-title":"Immunomodulation and immune reconstitution in chronic lymphocytic leukemia","volume":"51","author":"Riches","year":"2014","journal-title":"Semin Hematol"},{"key":"B16","volume-title":"SEER Cancer Statistics Review (CSR) 1975-2018","author":"Howlader","year":"2020"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v94.2.448.414k13_448_454","article-title":"Clinical characteristics and outcome of young chronic lymphocytic leukemia patients: a single institution study of 204 cases","volume":"94","author":"Mauro","year":"1999","journal-title":"Blood"},{"key":"B18","article-title":"Chronic lymphoid leukemia in young subjects","volume":"29","author":"Drancourt","year":"1987","journal-title":"Nouv Rev Fr Hematol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2013.086066","article-title":"Chronic lymphocytic leukemia in young (<\/= 55 years) patients: a comprehensive analysis of prognostic factors and outcomes","volume":"99","author":"Parikh","year":"2014","journal-title":"Haematologica"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.885150","article-title":"Distinct age-related clinical features and risk assessment in Chinese with chronic lymphocytic leukemia","volume":"12","author":"Tian","year":"2022","journal-title":"Front Oncol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1186\/s12885-017-3176-x","article-title":"Characterizing and prognosticating chronic lymphocytic leukemia in the elderly: prospective evaluation on 455 patients treated in the United States","volume":"17","author":"Nabhan","year":"2017","journal-title":"BMC Cancer"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2014.107326","article-title":"Chronic lymphocytic leukemia in the elderly: clinico-biological features, outcomes, and proposal of a prognostic model","volume":"99","author":"Baumann","year":"2014","journal-title":"Haematologica"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v78.6.1545.bloodjournal7861545","article-title":"Presenting features and prognosis of chronic lymphocytic leukemia in younger adults [see comments","volume":"78","author":"Montserrat","year":"1991","journal-title":"Blood"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v97.9.2777","article-title":"Survivin is expressed on CD40 stimulation and interfaces proliferation and apoptosis in B-cell chronic lymphocytic leukemia","volume":"97","author":"Granziero","year":"2001","journal-title":"Blood"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1403189","article-title":"TLR-9 and IL-15 synergy promotes the in vitro clonal expansion of chronic lymphocytic leukemia B cells","volume":"195","author":"Mongini","year":"2015","journal-title":"J Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-09-806398","article-title":"Guidelines for diagnosis, indications for treatment, response assessment and supportive management of chronic lymphocytic leukemia","volume":"131","author":"Hallek","year":"2018","journal-title":"Blood"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.10720","article-title":"Genomic aberrations and survival in chronic lymphocytic leukemia","volume":"343","author":"Dohner","year":"2000","journal-title":"N Engl J Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v94.6.1840","article-title":"Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia","volume":"94","author":"Damle","year":"1999","journal-title":"Blood"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.crmeth.2024.100883","article-title":"CENCAT enables immunometabolic profiling by measuring protein synthesis via bioorthogonal noncanonical amino acid tagging","volume":"4","author":"Vrieling","year":"2024","journal-title":"Cell Rep Methods"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2025.104134","article-title":"Protocol for measuring cellular energetics through noncanonical amino acid tagging in human peripheral blood and murine tissue immune cells","volume":"6","author":"Vrieling","year":"2025","journal-title":"STAR Protoc"},{"key":"B31","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.ccr.2012.02.014","article-title":"Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate","volume":"21","author":"Ward","year":"2012","journal-title":"Cancer Cell"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2015.07.034","article-title":"Glucose, glycolysis and lymphocyte responses","volume":"68","author":"Donnelly","year":"2015","journal-title":"Mol Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2024-004567","article-title":"Induction of interleukin 21 receptor expression via enhanced intracellular metabolism in B cells and its relevance to the disease activity in systemic lupus erythematosus","volume":"10","author":"Ueno","year":"2024","journal-title":"RMD Open"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021013990","article-title":"Characterization of metabolic alterations of chronic lymphocytic leukemia in the lymph node microenvironment","volume":"140","author":"Chen","year":"2022","journal-title":"Blood"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-08-449744","article-title":"IGHV unmutated and mutated chronic lymphocytic leukemia cells produce activation-induced deaminase protein with a full range of biologic functions","volume":"120","author":"Patten","year":"2012","journal-title":"Blood"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-09-876292","article-title":"Ibrutinib therapy downregulates AID enzyme and proliferative fractions in chronic lymphocytic leukemia","volume":"133","author":"Morande","year":"2019","journal-title":"Blood"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0156-5","article-title":"Second signals rescue B cells from activation-induced mitochondrial dysfunction and death","volume":"19","author":"Akkaya","year":"2018","journal-title":"Nat Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1302062","article-title":"Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells","volume":"192","author":"Caro-Maldonado","year":"2014","journal-title":"J Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-05-284984","article-title":"The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia","volume":"117","author":"Herishanu","year":"2011","journal-title":"Blood"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation-2010.1.82","article-title":"Treatment of younger patients with chronic lymphocytic leukemia","author":"Ferrajoli","year":"2010","journal-title":"Hematol Am Soc Hematol Educ Program"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0609.1994.tb00648.x","article-title":"Comparison of younger versus older B-cell chronic lymphocytic leukemia patients for clinical presentation and prognosis. A retrospective study of 53 cases","volume":"52","author":"Molica","year":"1994","journal-title":"Eur J Haematol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V120.21.1785.1785","article-title":"The metabolic signature of CLL: Enhanced glucose metabolism in a subset of high-risk CLL patients","volume":"120","author":"Liu","year":"2012","journal-title":"Blood"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-10-532200","article-title":"Stromal cell-mediated glycolytic switch in CLL cells involves Notch-c-Myc signaling","volume":"125","author":"Jitschin","year":"2015","journal-title":"Blood"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.203067","article-title":"Energy metabolism is co-determined by genetic variants in chronic lymphocytic leukemia and influences drug sensitivity","volume":"104","author":"Lu","year":"2019","journal-title":"Haematologica"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-017-0006-x","article-title":"The twilight of immunity: emerging concepts in aging of the immune system","volume":"19","author":"Nikolich-Zugich","year":"2018","journal-title":"Nat Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of aging: An expanding universe","volume":"186","author":"Lopez-Otin","year":"2023","journal-title":"Cell"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-020-0873-2","article-title":"T-cells in chronic lymphocytic leukemia: Guardians or drivers of disease","volume":"34","author":"Roessner","year":"2020","journal-title":"Leukemia"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-01-622936","article-title":"Mechanisms of PD-L1\/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Emicro-TCL1 CLL mouse model","volume":"126","author":"McClanahan","year":"2015","journal-title":"Blood"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0250-6","article-title":"Control of chronic lymphocytic leukemia development by clonally-expanded CD8(+) T-cells that undergo functional exhaustion in secondary lymphoid tissues","volume":"33","author":"Hanna","year":"2019","journal-title":"Leukemia"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-2630","article-title":"Expansion of a CD8(+)PD-1(+) replicative senescence phenotype in early stage CLL patients is associated with inverted CD4:CD8 ratios and disease progression","volume":"18","author":"Nunes","year":"2012","journal-title":"Clin Cancer Res"},{"key":"B51","doi-asserted-by":"publisher","first-page":"7271","DOI":"10.1038\/s41467-025-61822-x","article-title":"Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy target","volume":"16","author":"Llao-Cid","year":"2025","journal-title":"Nat Commun"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1005752","article-title":"mixOmics: An R package for 'omics feature selection and multiple data integration","volume":"13","author":"Rohart","year":"2017","journal-title":"PLoS Comput Biol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1936737\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T05:34:34Z","timestamp":1788759274000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1936737\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,7]]},"references-count":52,"alternative-id":["10.3389\/fimmu.2026.1936737"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1936737","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,7]]},"article-number":"1936737"}}