{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T17:37:26Z","timestamp":1769621846902,"version":"3.49.0"},"reference-count":24,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T00:00:00Z","timestamp":1769385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"crossref","award":["307\/22"],"award-info":[{"award-number":["307\/22"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001698","name":"Israel Cancer Research Fund","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001698","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Israel Precision Medicine Partnership"},{"name":"Israel Ministry of Science and Technology Nofar program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>More than 90% of bladder cancers are classified as urothelial carcinomas (UC), with approximately 75% of these cases presenting as non-muscle-invasive bladder cancer (NMIBC). Bacillus Calmette\u2013Gu\u00e9rin (BCG) is the current standard immunotherapy for NMIBC, yet it suffers from limited efficacy, frequent tumor recurrence, and substantial toxicity. These limitations underscore the need for safer, more effective, and accessible alternatives. We investigated whether uropathogenic Escherichia coli (UPEC), a natural inducer of immune responses in the bladder, could serve as a novel intravesical immunotherapeutic agent. Using orthotopic bladder cancer models in both mice (MB49-luc) and rats (AY-27), we evaluated the efficacy, specificity, immune dependence, and safety of formaldehyde-inactivated UPEC strains, including mutants with altered type 1 fimbriae expression. Intravesical administration of inactivated UPEC significantly reduced tumor burden and prolonged survival, outperforming BCG in murine models and demonstrating equivalent efficacy with markedly reduced toxicity in rats. The antitumor effect was T cell-dependent and partially mediated by type I fimbriae, which facilitated tumor-specific adhesion. Notably, systemic (subcutaneous) administration of UPEC abrogated efficacy and increased mortality, emphasizing the necessity of localized bladder delivery. In conclusion, we identify inactivated UPEC as a potent, tumor-targeting, and T cell-dependent immunotherapeutic agent with a superior safety profile compared to BCG. This approach might represent a promising and practical alternative for bladder cancer treatment.<\/jats:p>","DOI":"10.3390\/cells15030229","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T10:24:36Z","timestamp":1769423076000},"page":"229","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Bladder Cancer with Inactivated Uropathogenic E. coli: A Novel Alternative to BCG Immunotherapy"],"prefix":"10.3390","volume":"15","author":[{"given":"Vladimir","family":"Yutkin","sequence":"first","affiliation":[{"name":"Department of Urology, Hadassah Hebrew University Medical School, Jerusalem 91120, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naseem","family":"Maalouf","sequence":"additional","affiliation":[{"name":"The Institute of Dental Sciences, The Hebrew University-Hadassah School of Dental Medicine, Jerusalem 91120, Israel"},{"name":"Department of Oral and Maxillofacial Surgery, Tzafon Medical Center, Tveria 1520801, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chamutal","family":"Gur","sequence":"additional","affiliation":[{"name":"The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Hebrew University Hadassah Medical School (IMRIC), Jerusalem 91120, Israel"},{"name":"The Rheumatology Research Center, Hadassah-Hebrew University, Jerusalem 91120, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Avraham","family":"Zini","sequence":"additional","affiliation":[{"name":"The Institute of Dental Sciences, The Hebrew University-Hadassah School of Dental Medicine, Jerusalem 91120, Israel"},{"name":"Department of Community Dentistry, Hadassah Medical Center, Faculty of Dental Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1350-2280","authenticated-orcid":false,"given":"Gilad","family":"Bachrach","sequence":"additional","affiliation":[{"name":"The Institute of Dental Sciences, The Hebrew University-Hadassah School of Dental Medicine, Jerusalem 91120, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ofer","family":"Mandelboim","sequence":"additional","affiliation":[{"name":"The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Hebrew University Hadassah Medical School (IMRIC), Jerusalem 91120, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,26]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"The Treatment of Inoperable Sarcoma by Bacterial Toxins (the Mixed Toxins of the Streptococcus erysipelas and the Bacillus prodigiosus)","volume":"3","author":"Coley","year":"1910","journal-title":"Proc. R. Soc. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1159\/000049008","article-title":"Fever, cancer incidence and spontaneous remissions","volume":"9","author":"Kleef","year":"2001","journal-title":"Neuroimmunomodulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1111\/j.0954-6820.1936.tb15958.x","article-title":"Employment of B. C. G. especially in Intravenous Injection","volume":"90","author":"Holmgren","year":"1936","journal-title":"Acta Medica Scand."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/j.eururo.2011.03.017","article-title":"EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update","volume":"59","author":"Babjuk","year":"2011","journal-title":"Eur. Urol."},{"key":"ref_5","first-page":"12","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.ejca.2018.07.005","article-title":"Cancer incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018","volume":"103","author":"Ferlay","year":"2018","journal-title":"Eur. J. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Zhou, Z., Zheng, L., Gong, Z., Li, Y., Jin, Y., Huang, Y., and Chi, M. (2023). Urinary Tract Infections Caused by Uropathogenic Escherichia coli: Mechanisms of Infection and Treatment Options. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310537"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1001\/jama.2020.17598","article-title":"Bladder Cancer: A Review","volume":"324","author":"Lenis","year":"2020","journal-title":"JAMA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1097\/01.ju.0000162059.64886.1c","article-title":"Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: A meta-analysis of the published results of randomized clinical trials","volume":"174","author":"Sylvester","year":"2005","journal-title":"J. Urol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1111\/apm.13011","article-title":"Bacillus Calmette-Guerin immunotherapy for bladder cancer: A review of immunological aspects, clinical effects and BCG infections","volume":"128","author":"Larsen","year":"2020","journal-title":"APMIS"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2660","DOI":"10.1016\/j.juro.2007.07.118","article-title":"The expression level of ligands for natural killer cell receptors predicts response to bacillus Calmette-Guerin therapy: A pilot study","volume":"178","author":"Yutkin","year":"2007","journal-title":"J. Urol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1002\/eji.201040773","article-title":"IL-17 production by gammadelta T cells is important for the antitumor effect of Mycobacterium bovis bacillus Calmette-Guerin treatment against bladder cancer","volume":"41","author":"Takeuchi","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"ref_13","first-page":"1469","article-title":"Significance of target cell infection and natural killer cells in the anti-tumor effects of bacillus Calmette-Guerin in murine bladder cancer","volume":"17","author":"Sonoda","year":"2007","journal-title":"Oncol. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Maalouf, N., Gur, C., Yutkin, V., Scaiewicz, V., Mandelboim, O., and Bachrach, G. (2022). High mannose level in bladder cancer enhances type 1 fimbria-mediated attachment of uropathogenic E. coli. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.968739"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.chom.2013.11.004","article-title":"Natural killer cell-mediated host defense against uropathogenic E. coli is counteracted by bacterial hemolysinA-dependent killing of NK cells","volume":"14","author":"Gur","year":"2013","journal-title":"Cell Host Microbe"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.1002\/eji.202049006","article-title":"The inhibitory receptor CD300a is essential for neutrophil-mediated clearance of urinary tract infection in mice","volume":"51","author":"Isaacson","year":"2021","journal-title":"Eur. J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.celrep.2017.06.034","article-title":"Stromal Cell-Derived Factor 1 Mediates Immune Cell Attraction upon Urinary Tract Infection","volume":"20","author":"Isaacson","year":"2017","journal-title":"Cell Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3344","DOI":"10.1128\/IAI.70.7.3344-3354.2002","article-title":"Assessment of virulence of uropathogenic Escherichia coli type 1 fimbrial mutants in which the invertible element is phase-locked on or off","volume":"70","author":"Gunther","year":"2002","journal-title":"Infect. Immun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7588","DOI":"10.1128\/IAI.73.11.7588-7596.2005","article-title":"Coordinate expression of fimbriae in uropathogenic Escherichia coli","volume":"73","author":"Snyder","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2838","DOI":"10.1128\/IAI.69.5.2838-2846.2001","article-title":"In vivo dynamics of type 1 fimbria regulation in uropathogenic Escherichia coli during experimental urinary tract infection","volume":"69","author":"Gunther","year":"2001","journal-title":"Infect. Immun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1128\/jb.103.2.447-456.1970","article-title":"Selective outgrowth of fimbriate bacteria in static liquid medium","volume":"103","author":"Old","year":"1970","journal-title":"J. Bacteriol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1093\/jjco\/hyt086","article-title":"Adverse reactions related to treatment compliance during BCG maintenance therapy for non-muscle-invasive bladder cancer","volume":"43","author":"Miyazaki","year":"2013","journal-title":"Jpn. J. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hatherill, M., Tait, D., and McShane, H. (2016). Clinical Testing of Tuberculosis Vaccine Candidates. Tuberc. Tuber. Bacillus, 4.","DOI":"10.1128\/microbiolspec.TBTB2-0015-2016"},{"key":"ref_24","first-page":"881","article-title":"Validation of Free Formaldehyde Determination Method in DT Vaccine and Tetanus Toxoid Antigen","volume":"78","author":"Zali","year":"2023","journal-title":"Arch. Razi Inst."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/3\/229\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T05:11:26Z","timestamp":1769577086000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/3\/229"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,26]]},"references-count":24,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["cells15030229"],"URL":"https:\/\/doi.org\/10.3390\/cells15030229","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,26]]}}}