{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:53:36Z","timestamp":1791287616161,"version":"4.1.0"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"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>Intravesical Bacillus Calmette\u2013Gu\u00e9rin (BCG) remains the standard adjuvant treatment for high-risk non-muscle-invasive bladder cancer (NMIBC), yet the mechanisms underlying its durable clinical benefit and treatment resistance remain incompletely understood. Although BCG has traditionally been regarded as a local immunotherapy, emerging clinical and preclinical evidence suggests that intravesical BCG can induce trained-immunity-associated systemic immune changes, including alterations in circulating innate immune responses and hematopoietic programming. In this Review, we propose the bone marrow\u2013bladder axis as a hypothesis-generating conceptual framework linking local microbial sensing with systemic hematopoietic responses that may contribute to sustained myeloid and adaptive antitumor immunity. Building upon this framework, we further introduce the Failure-to-Train (FTT) model, which proposes that selected immune-training-related mechanisms may contribute to heterogeneous patterns of BCG failure through disruption of productive immune training at distinct stages of the proposed immune-training circuit. Finally, we discuss the implications of this framework for biomarker development, experimental validation and mechanism-guided immunotherapy. By considering systemic immune training as a potential contributor to BCG responses, this Review provides a conceptual framework for investigating treatment response and resistance and for developing testable strategies for next-generation immunotherapy.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1945559","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:18:18Z","timestamp":1791285498000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Reprogramming innate immune memory in bladder cancer: the proposed bone marrow\u2013bladder axis and next-generation BCG-based immunotherapies"],"prefix":"10.3389","volume":"17","author":[{"given":"Meng","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Geriatric, Xiangyang No. 1 People\u2019s Hospital, Hubei University of Medicine","place":["Xiangyang, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Colorectal and Anal Surgery, Xiangyang No. 1 People\u2019s Hospital, Hubei University of Medicine","place":["Xiangyang, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-zhao","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Urology, Xiangyang No. 1 People\u2019s Hospital, Hubei University of Medicine","place":["Xiangyang, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Li","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of General Practice, Xiangyang No. 1 People\u2019s Hospital, Hubei University of Medicine","place":["Xiangyang, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dai-Ju","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Emergency, Xiangyang No. 1 People\u2019s Hospital, Hubei University of Medicine","place":["Xiangyang, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Jia","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Urology, Xiangyang No. 1 People\u2019s Hospital, Hubei University of Medicine","place":["Xiangyang, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nrurol.2014.15","article-title":"The mechanism of action of BCG therapy for bladder cancer--a current perspective","volume":"11","author":"Redelman-Sidi","year":"2014","journal-title":"Nat Rev Urol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1128\/cmr.00194-23","article-title":"Review of BCG immunotherapy for bladder cancer","volume":"38","author":"Liatsos","year":"2025","journal-title":"Clin Microbiol Rev"},{"key":"B3","doi-asserted-by":"publisher","first-page":"3073","DOI":"10.3390\/cancers14133073","article-title":"BCG in bladder cancer immunotherapy","volume":"14","author":"Jiang","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.71243","article-title":"Mechanisms, clinical trials, and new treatments for BCG-unresponsive in nonmuscle invasive bladder cancer","volume":"14","author":"Huang","year":"2025","journal-title":"Cancer Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41585-018-0055-4","article-title":"Mechanisms of BCG immunotherapy and its outlook for bladder cancer","volume":"15","author":"Pettenati","year":"2018","journal-title":"Nat Rev Urol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1097\/MOU.0000000000000595","article-title":"Bacillus Calmette-Guerin treatment of bladder cancer: a systematic review and commentary on recent publications","volume":"29","author":"Mukherjee","year":"2019","journal-title":"Curr Opin Urol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-005518","article-title":"Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections","volume":"11","author":"van Puffelen","year":"2023","journal-title":"J Immunother Cancer"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1202157","article-title":"Intravesical BCG in bladder cancer induces innate immune responses against SARS-CoV-2","volume":"14","author":"Pichler","year":"2023","journal-title":"Front Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2025.05.002","article-title":"Microbial cancer immunotherapy reprograms hematopoiesis to enhance myeloid-driven anti-tumor immunity","volume":"43","author":"Daman","year":"2025","journal-title":"Cancer Cell"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0285-6","article-title":"Defining trained immunity and its role in health and disease","volume":"20","author":"Netea","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf1098","article-title":"Trained immunity: A program of innate immune memory in health and disease","volume":"352","author":"Netea","year":"2016","journal-title":"Science"},{"key":"B12","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/s41581-022-00633-5","article-title":"Trained immunity - basic concepts and contributions to immunopathology","volume":"19","author":"Ochando","year":"2023","journal-title":"Nat Rev Nephrol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.12.031","article-title":"BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis","volume":"172","author":"Kaufmann","year":"2018","journal-title":"Cell"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41585-020-0346-4","article-title":"Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer","volume":"17","author":"van Puffelen","year":"2020","journal-title":"Nat Rev Urol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.euo.2026.05.005","article-title":"Individual patient data validation of the EAU definitions of BCG failure in patients with non-muscle-invasive urothelial carcinoma of the bladder: An international multicenter retrospective study","volume":"9","author":"Gontero","year":"2026","journal-title":"Eur Urol Oncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1097\/ju.0000000000004452","article-title":"Diagnosis and treatment of non-muscle invasive bladder cancer: AUA\/SUO guideline: 2024 amendment","volume":"211","author":"Holzbeierlein","year":"2024","journal-title":"J Urol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-5347(05)67707-5","article-title":"Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group study","volume":"163","author":"Lamm","year":"2000","journal-title":"J Urol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-5347(05)64273-5","article-title":"Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials","volume":"168","author":"Sylvester","year":"2002","journal-title":"J Urol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2009.04.038","article-title":"An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive bladder cancer","volume":"56","author":"Malmstrom","year":"2009","journal-title":"Eur Urol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"12596","DOI":"10.3390\/ijms241612596","article-title":"BCG-unresponsive non-muscle-invasive bladder cancer: current treatment landscape and novel emerging molecular targets","volume":"24","author":"Claps","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1200\/edbk-25-471942","article-title":"New treatment options for non-muscle-invasive bladder cancer","volume":"45","author":"Filon","year":"2025","journal-title":"Am Soc Clin Oncol Educ Book"},{"key":"B22","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.immuni.2020.10.011","article-title":"The intersection of epigenetics and metabolism in trained immunity","volume":"54","author":"Fanucchi","year":"2021","journal-title":"Immunity"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1126\/science.1251086","article-title":"Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity","volume":"345","author":"Saeed","year":"2014","journal-title":"Science"},{"key":"B24","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.ceb.2019.12.006","article-title":"Advances in understanding molecular regulation of innate immune memory","volume":"63","author":"Dominguez-Andres","year":"2020","journal-title":"Curr Opin Cell Biol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1126\/science.1250684","article-title":"mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity","volume":"345","author":"Cheng","year":"2014","journal-title":"Science"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.10.008","article-title":"Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity","volume":"24","author":"Arts","year":"2016","journal-title":"Cell Metab"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.11.025","article-title":"Metabolic induction of trained immunity through the mevalonate pathway","volume":"172","author":"Bekkering","year":"2018","journal-title":"Cell"},{"key":"B28","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.chom.2017.12.010","article-title":"BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity","volume":"23","author":"Arts","year":"2018","journal-title":"Cell Host Microbe"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.31083\/fbl26995","article-title":"Role of tumor-associated macrophages in breast cancer immunotherapy","volume":"30","author":"He","year":"2025","journal-title":"Front Biosci (Landmark Ed)"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.31083\/fbl44127","article-title":"Biophysical properties of the extracellular matrix in cancer: Insights into immunotherapy","volume":"30","author":"Zheng","year":"2025","journal-title":"Front Biosci (Landmark Ed)"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/nri3887","article-title":"The nature of immune responses to urinary tract infections","volume":"15","author":"Abraham","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1863","article-title":"The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors","volume":"11","author":"Kawai","year":"2010","journal-title":"Nat Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-1416","article-title":"Neutrophil granulocytes are required for effective Bacillus Calmette-Guerin immunotherapy of bladder cancer and orchestrate local immune responses","volume":"66","author":"Suttmann","year":"2006","journal-title":"Cancer Res"},{"key":"B34","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/nrclinonc.2016.217","article-title":"Tumour-associated macrophages as treatment targets in oncology","volume":"14","author":"Mantovani","year":"2017","journal-title":"Nat Rev Clin Oncol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3233\/blc-200277","article-title":"The urinary microbiome and bladder cancer: susceptibility and immune responsiveness","volume":"6","author":"Andolfi","year":"2020","journal-title":"Bladder Cancer"},{"key":"B36","doi-asserted-by":"publisher","first-page":"291\u2013","DOI":"10.1016\/j.urolonc.2024.04.011","article-title":"An exploratory study investigating the impact of the bladder tumor microbiome on Bacillus Calmette Guerin (BCG) response in non-muscle invasive bladder cancer","volume":"42","author":"Knorr","year":"2024","journal-title":"Urol Oncol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.570077","article-title":"Association between antibiotic treatment and the efficacy of intravesical BCG therapy in patients with high-risk non-muscle invasive bladder cancer","volume":"11","author":"Pak","year":"2021","journal-title":"Front Oncol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.34897","article-title":"Systemic versus localized Bacillus Calmette Guerin immunotherapy of bladder cancer promotes an anti-tumoral microenvironment: novel role of trained immunity","volume":"155","author":"Atallah","year":"2024","journal-title":"Int J Cancer"},{"key":"B39","doi-asserted-by":"publisher","first-page":"699","DOI":"10.3390\/cells13080699","article-title":"Breaking barriers: modulation of tumor microenvironment to enhance Bacillus Calmette-Guerin immunotherapy of bladder cancer","volume":"13","author":"Ibrahim","year":"2024","journal-title":"Cells"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.615091","article-title":"Immunological hallmarks for clinical response to BCG in bladder cancer","volume":"11","author":"Lim","year":"2020","journal-title":"Front Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-19-1920","article-title":"Adaptive immune resistance to intravesical BCG in non-muscle invasive bladder cancer: implications for prospective BCG-unresponsive trials","volume":"26","author":"Kates","year":"2020","journal-title":"Clin Cancer Res"},{"key":"B42","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s00262-019-02443-4","article-title":"Mechanisms of immune evasion in bladder cancer","volume":"69","author":"Crispen","year":"2020","journal-title":"Cancer Immunol Immunother"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.01270","article-title":"Immune responses in bladder cancer-role of immune cell populations, prognostic factors and therapeutic implications","volume":"9","author":"Joseph","year":"2019","journal-title":"Front Oncol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"391\u2013","DOI":"10.1016\/j.urolonc.2025.01.015","article-title":"Impact of baseline PD-L1 status in BCG naive nonmuscle invasive bladder cancer on outcomes and changes after BCG exposure","volume":"43","author":"Gerald","year":"2025","journal-title":"Urol Oncol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2015.64.4070","article-title":"Definitions, end points, and clinical trial designs for non-muscle-invasive bladder cancer: recommendations from the International Bladder Cancer Group","volume":"34","author":"Kamat","year":"2016","journal-title":"J Clin Oncol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.urolonc.2014.02.020","article-title":"BCG-refractory vs. BCG-relapsing non-muscle-invasive bladder cancer: a prospective cohort outcomes study","volume":"33","author":"Herr","year":"2015","journal-title":"Urol Oncol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.842182","article-title":"Bacillus Calmette-Guerin treatment changes the tumor microenvironment of non-muscle-invasive bladder cancer","volume":"12","author":"Su","year":"2022","journal-title":"Front Oncol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1172\/jci145666","article-title":"BCG therapy downregulates HLA-I on Malignant cells to subvert antitumor immune responses in bladder cancer","volume":"132","author":"Rouanne","year":"2022","journal-title":"J Clin Invest"},{"key":"B49","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.euo.2021.12.006","article-title":"A phase 1\/2 single-arm clinical trial of recombinant Bacillus Calmette-Guerin (BCG) VPM1002BC immunotherapy in non-muscle-invasive bladder cancer recurrence after conventional BCG therapy: SAKK 06\/14","volume":"5","author":"Rentsch","year":"2022","journal-title":"Eur Urol Oncol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.juro.2012.09.049","article-title":"Connaught and Russian strains showed the highest direct antitumor effects of different Bacillus Calmette-Guerin substrains","volume":"189","author":"Secanella-Fandos","year":"2013","journal-title":"J Urol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2014.02.061","article-title":"Bacillus Calmette-Guerin strain differences have an impact on clinical outcome in bladder cancer immunotherapy","volume":"66","author":"Rentsch","year":"2014","journal-title":"Eur Urol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1016\/j.urolonc.2016.05.033","article-title":"The efficacy of BCG TICE and BCG Connaught in a cohort of 2,099 patients with T1G3 non-muscle-invasive bladder cancer","volume":"34","author":"Witjes","year":"2016","journal-title":"Urol Oncol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1056\/evidoa2200167","article-title":"IL-15 Superagonist NAI in BCG-unresponsive non-muscle-invasive bladder cancer","volume":"2","author":"Chamie","year":"2023","journal-title":"NEJM Evid"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-25-1231","article-title":"FDA approval summary: Nogapendekin alfa inbakicept-pmln with BCG for BCG-unresponsive carcinoma in situ","volume":"31","author":"Heiss","year":"2025","journal-title":"Clin Cancer Res"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.mct-21-0780","article-title":"Pharmacologic activation of STING in the bladder induces potent antitumor immunity in non-muscle invasive murine bladder cancer","volume":"21","author":"Huang","year":"2022","journal-title":"Mol Cancer Ther"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.can-24-1022","article-title":"STING agonist VB-85247 induces durable antitumor immune responses by intravesical administration in a non-muscle-invasive bladder cancer","volume":"85","author":"Prabagar","year":"2025","journal-title":"Cancer Res"},{"key":"B57","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.annonc.2025.09.017","article-title":"ALBAN (GETUG-AFU 37): a phase III, randomized, open-label international trial of intravenous atezolizumab and intravesical Bacillus Calmette-Guerin (BCG) versus BCG alone in BCG-naive high-risk, non-muscle-invasive bladder cancer (NMIBC)","volume":"37","author":"Roupret","year":"2026","journal-title":"Ann Oncol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-025-03738-z","article-title":"Sasanlimab plus BCG in BCG-naive, high-risk non-muscle invasive bladder cancer: the randomized phase 3 CREST trial","volume":"31","author":"Shore","year":"2025","journal-title":"Nat Med"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(25)01897-5","article-title":"Durvalumab in combination with BCG for BCG-naive, high-risk, non-muscle-invasive bladder cancer (POTOMAC): final analysis of a randomised, open-label, phase 3 trial","volume":"406","author":"De Santis","year":"2025","journal-title":"Lancet"},{"key":"B60","article-title":"FDA approves durvalumab in combination with Bacillus Calmette-Guerin for high-risk non-muscle invasive bladder cancer: U.S. Food and Drug Administration; 2026 [updated May 28, 2026. Available from: FDA","year":"2026"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2026.01.009","article-title":"Bacillus Calmette-Guerin plus Mitomycin versus Bacillus Calmette-Guerin alone for Bacillus Calmette-Guerin-naive non-muscle-invasive bladder cancer: a randomised phase 3 trial (ANZUP 1301)","volume":"89","author":"Hayne","year":"2026","journal-title":"Eur Urol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1945559\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:18:20Z","timestamp":1791285500000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1945559\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,6]]},"references-count":61,"alternative-id":["10.3389\/fimmu.2026.1945559"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1945559","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,6]]},"article-number":"1945559"}}