{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T13:52:16Z","timestamp":1793022736311,"version":"4.5.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Intravesical Bacillus Calmette-Gu\u00e9rin (BCG) immunotherapy remains one of the most effective treatments for non-muscle invasive bladder cancer (NMIBC). However, a substantial proportion of patients fail to respond, and the precise mechanisms underlying BCG\u2019s therapeutic effects remain incompletely understood. While extracellular vesicles (EVs) can modulate a range of biological processes, their relevance in this context is also poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To investigate the interplay between BCG, EVs, and bladder cancer, bladder cancer (BC) cell lines, dendritic cell (DC) and T cell co-culture systems, nanoparticle tracking analysis, molecular profiling, and Western blotting approaches were employed\n                      <jats:italic>in vitro<\/jats:italic>\n                      . Subcutaneous MB49 tumor models in mice were additionally used to assess the impact of exogenously administered BCG-induced EVs on DC activation, T cell proliferation, and antitumor efficacy\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified a novel mechanism of action involving BCG-induced EVs (EVs\n                      <jats:sup>BCG<\/jats:sup>\n                      ). Following BCG internalization by bladder cancer (BC) cells, a robust immune cascade is triggered, accompanied by a surge in EV secretion and altered cargo composition. These EVs\n                      <jats:sup>BCG<\/jats:sup>\n                      were found to be enriched with key immunomodulatory proteins, including MHC class I and II molecules as well as co-stimulatory molecules CD80 and CD86. Functionally, we found that EVs\n                      <jats:sup>BCG<\/jats:sup>\n                      were capable of activating DCs, thereby enhancing T cell activity\n                      <jats:italic>in vitro<\/jats:italic>\n                      . Moreover, pre-treatment of mice with EVs\n                      <jats:sup>BCG<\/jats:sup>\n                      significantly potentiated the therapeutic efficacy of BCG in a syngeneic murine bladder cancer model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings implicate EVs\n                      <jats:sup>BCG<\/jats:sup>\n                      as critical intermediaries in the anti-tumor immune response and suggest their potential utility as mediators and\/or predictive biomarkers for therapeutic efficacy. In summary, we propose a previously unrecognized mechanism of BCG immunotherapy mediated by EVs, establishing them as pivotal components of the immune signaling network driving effective treatment outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1707754","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T05:46:27Z","timestamp":1776059187000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Bacillus Calmette-Gu\u00e9rin immunotherapy-induced extracellular vesicles promote antitumor immunity in bladder cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Carlos J.","family":"Ortiz-Bonilla","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Rochester Medical Center","place":["Rochester, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan D.","family":"Molony","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Rochester Medical Center","place":["Rochester, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Rochester Medical Center","place":["Rochester, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Messing","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Rochester Medical Center","place":["Rochester, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Fen","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Rochester Medical Center","place":["Rochester, NY, United States"]},{"name":"Department of Urology, University of Rochester Medical Center","place":["Rochester, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djq495","article-title":"Projections of the cost of cancer care in the United States: 2010-2020","volume":"103","author":"Mariotto","year":"2011","journal-title":"J Natl Cancer Inst"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-19-1534","article-title":"Medical care costs associated with cancer survivorship in the United States","volume":"29","author":"Mariotto","year":"2020","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.28147","article-title":"Recurrence of high-risk bladder cancer: a population-based analysis","volume":"119","author":"Chamie","year":"2013","journal-title":"Cancer"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2017.04.015","article-title":"Prognostic performance and reproducibility of the 1973 and 2004\/2016 World Health Organization grading classification systems in non-muscle-invasive bladder cancer: a European Association of Urology Non-muscle Invasive Bladder Cancer Guidelines Panel systematic review","volume":"72","author":"Soukup","year":"2017","journal-title":"Eur Urol"},{"key":"B5","article-title":"History of BCG vaccine","volume":"8","author":"Luca","year":"2013","journal-title":"Maedica (Bucur)"},{"key":"B6","article-title":"Bacillus Calmette Guerin","volume-title":"StatPearls","author":"Okafor","year":"2022"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1097\/00000658-197410000-00029","article-title":"BCG immunotherapy of Malignant melanoma: summary of a seven-year experience","volume":"180","author":"Morton","year":"1974","journal-title":"Ann Surg"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-5347(17)58737-6","article-title":"Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors","volume":"116","author":"Morales","year":"1976","journal-title":"J Urol"},{"key":"B9","first-page":"SECTION 3, 3","article-title":"F.D.A. 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