{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T12:03:18Z","timestamp":1790337798701,"version":"4.1.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"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>Interferon-\u03b3 (IFN-\u03b3) is a central mediator of antitumor immunity in bladder cancer, but an IFN-\u03b3-rich tumor microenvironment does not necessarily translate into tumor control. Tissue-level inflammatory signatures capture overall immune activity and cannot determine whether malignant urothelial cells remain responsive to immune-derived IFN-\u03b3 or preserve the downstream functions required for immune elimination. This Mini Review examines tumor-intrinsic IFN-\u03b3-associated immunity at three functional checkpoints: proximal IFN-\u03b3 sensing and signal transduction, chemokine-mediated effector-cell recruitment, and antigen-presentation-dependent tumor recognition. Bladder cancer models show that IFNGR\u2013JAK\u2013STAT1 responsiveness can be lost or attenuated, while separate tumor-intrinsic mechanisms can restrict CXCL9\/CXCL10-dependent T-cell recruitment without a demonstrated proximal signaling defect. Antigen presentation forms a further checkpoint, with HLA-I and antigen-processing machinery altered through transcriptional, treatment-associated, and post-translational mechanisms. These mechanisms do not constitute a single linear IFN-\u03b3 resistance pathway. They instead mark distinct points at which inflammatory pressure can become uncoupled from tumor elimination. IFN-\u03b3-responsive programs are also shaped by treatment context and signaling duration, as illustrated by CIITA\/MHC-II biology and prolonged interferon signaling. Resolving these processes at malignant-cell, spatial, and longitudinal levels may improve the interpretation of BCG and checkpoint-blockade resistance and support more selective combination strategies.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1979524","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T11:33:01Z","timestamp":1790335981000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Tumor-intrinsic execution of interferon-\u03b3-associated immunity in bladder cancer: checkpoints in signaling, recruitment, and recognition"],"prefix":"10.3389","volume":"17","author":[{"given":"Jingjing","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Reproductive Medicine, The Affiliated People\u2019s Hospital of Ningbo University","place":["Ningbo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichun","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Urology, The Affiliated People\u2019s Hospital of Ningbo University","place":["Ningbo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanshan","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine, The Affiliated People\u2019s Hospital of Ningbo University","place":["Ningbo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Urology, The Affiliated People\u2019s Hospital of Ningbo University","place":["Ningbo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14215295","article-title":"The urothelial transcriptomic response to interferon gamma: implications for bladder cancer prognosis and immunotherapy","volume":"14","author":"Baker","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B2","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1038\/s41598-021-04678-7","article-title":"Upregulation of IFN\u03b3-mediated chemokines dominate the immune transcriptome of muscle-invasive urothelial carcinoma","volume":"12","author":"Olkhov-Mitsel","year":"2022","journal-title":"Sci Rep"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1038\/s41467-025-56462-0","article-title":"Predicting immunotherapy response of advanced bladder cancer through a meta-analysis of six independent cohorts","volume":"16","author":"Boll","year":"2025","journal-title":"Nat Commun"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30065-7","article-title":"Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial","volume":"18","author":"Sharma","year":"2017","journal-title":"Lancet Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-3089","article-title":"Putative biomarkers of clinical benefit with pembrolizumab in advanced urothelial cancer: results from the KEYNOTE-045 and KEYNOTE-052 landmark trials","volume":"28","author":"Bellmunt","year":"2022","journal-title":"Clin Cancer Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1038\/s41467-024-45714-0","article-title":"Gene-expression-based T-Cell-to-Stroma Enrichment (TSE) score predicts response to immune checkpoint inhibitors in urothelial cancer","volume":"15","author":"Rijnders","year":"2024","journal-title":"Nat Commun"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nature25501","article-title":"TGF\u03b2 attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells","volume":"554","author":"Mariathasan","year":"2018","journal-title":"Nature"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2004421117","article-title":"Bacterial immunotherapy for cancer induces CD4-dependent tumor-specific immunity through tumor-intrinsic interferon-\u03b3 signaling","volume":"117","author":"Antonelli","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02065","article-title":"Loss of Janus associated kinase 1 alters urothelial cell function and facilitates the development of bladder cancer","volume":"10","author":"Daza-Cajigal","year":"2019","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.cell.2016.08.069","article-title":"Loss of IFN-\u03b3 pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy","volume":"167","author":"Gao","year":"2016","journal-title":"Cell"},{"key":"B11","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1158\/2159-8290.CD-16-1223","article-title":"Primary resistance to PD-1 blockade mediated by JAK1\/2 mutations","volume":"7","author":"Shin","year":"2017","journal-title":"Cancer Discov"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2025.115445","article-title":"AGO2 mediates immunotherapy failure via suppressing tumor IFN-gamma response-dependent CD8+ T cell immunity","volume":"44","author":"Wang","year":"2025","journal-title":"Cell Rep"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2025.01.013","article-title":"Interferon-\u03b3\/Janus kinase 1\/STAT1 signaling represses Forkhead Box A1 and drives a basal transcriptional state in muscle-invasive bladder cancer","volume":"195","author":"Lawrence","year":"2025","journal-title":"Am J Pathol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.21037\/tcr-23-220","article-title":"A novel genes-based signature with prognostic value and predictive ability to select patients responsive to atezolizumab treatment in bladder cancer: an analysis on data from real-world studies","volume":"12","author":"Zhang","year":"2023","journal-title":"Transl Cancer Res"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2026.116443","article-title":"The ZNF737-CXCL10 axis drives immune exclusion and resistance to anti-PD-1 therapy in bladder cancer","volume":"175","author":"Gao","year":"2026","journal-title":"Int Immunopharmacol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2026.218729","article-title":"HDAC10 suppresses anti-tumour immunity by inhibiting ILF3-CXCL9 axis to block CD8+ T cell infiltration and activation in bladder cancer","volume":"657","author":"Zhuang","year":"2026","journal-title":"Cancer Lett"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2025-013809","article-title":"Targeting RRBP1 reverses immune evasion and enhances immunotherapy efficacy via the CXCL10-CXCR3 axis in bladder cancer","volume":"14","author":"Shen","year":"2026","journal-title":"J Immunother Cancer"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202300110","article-title":"S100A5 attenuates efficiency of anti-PD-L1\/PD-1 immunotherapy by inhibiting CD8+ T cell-mediated anti-cancer immunity in bladder carcinoma","volume":"10","author":"Li","year":"2023","journal-title":"Adv Sci (Weinh)"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-007230","article-title":"Bladder cancer intrinsic LRFN2 drives anticancer immunotherapy resistance by attenuating CD8+ T cell infiltration and functional transition","volume":"11","author":"Yu","year":"2023","journal-title":"J Immunother Cancer"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-023-01786-3","article-title":"Modulation of tumor microenvironment by targeting histone acetylation in bladder cancer","volume":"10","author":"Nunes","year":"2024","journal-title":"Cell Death Discov"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.20499","article-title":"Coordinated downregulation of the antigen presentation machinery and HLA class I\/\u03b22-microglobulin complex is responsible for HLA-ABC loss in bladder cancer","volume":"113","author":"Romero","year":"2005","journal-title":"Int J Cancer"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-0595","article-title":"Effect of human leukocyte antigen class I expression of tumor cells on outcome of intravesical instillation of bacillus Calmette-Guerin immunotherapy for bladder cancer","volume":"12","author":"Kitamura","year":"2006","journal-title":"Clin Cancer Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22147248","article-title":"Tumor escape phenotype in bladder cancer is associated with loss of HLA class I expression, T-cell exclusion and stromal changes","volume":"22","author":"Gil-Julio","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B24","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":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202519955","article-title":"O-GlcNAcylated TAP1 impairs antigen presentation and promotes immune evasion in bladder cancer","volume":"13","author":"Wu","year":"2026","journal-title":"Adv Sci (Weinh)"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1016\/j.ccell.2022.08.005","article-title":"NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer","volume":"40","author":"Salom\u00e9","year":"2022","journal-title":"Cancer Cell"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2026-014770","article-title":"Oncogenic PIK3CA mutation enhances tumor immunogenicity through the IRF1-NLRC5-MHC-I axis in urothelial carcinoma","volume":"14","author":"Su","year":"2026","journal-title":"J Immunother Cancer"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-22-0157","article-title":"BCG-induced tumor immunity requires tumor-intrinsic CIITA independent of MHC-II","volume":"10","author":"Redelman-Sidi","year":"2022","journal-title":"Cancer Immunol Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.114618","article-title":"Single-cell and spatial transcriptomic analysis reveal cellular heterogeneity and cancer cell-intrinsic major histocompatibility complex II expression in urothelial carcinoma","volume":"21","author":"Xiong","year":"2025","journal-title":"Int J Biol Sci"},{"key":"B30","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1038\/s41419-025-07821-8","article-title":"FGFR inhibitors promote the autophagic degradation of IFN-\u03b3-induced PD-L1 and alleviate the PD-L1-mediated transcriptional suppression of FGFR3-TACC3 in non-muscle-invasive bladder cancer","volume":"16","author":"Lin","year":"2025","journal-title":"Cell Death Dis"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00566-3","article-title":"Interferon-\u03b3: teammate or opponent in the tumour microenvironment","volume":"22","author":"Gocher","year":"2022","journal-title":"Nat Rev Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1190333","article-title":"Dysregulation in IFN-\u03b3 signaling and response: the barricade to tumor immunotherapy","volume":"14","author":"Han","year":"2023","journal-title":"Front Immunol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1540","DOI":"10.1016\/j.cell.2016.11.022","article-title":"Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade","volume":"167","author":"Benci","year":"2016","journal-title":"Cell"},{"key":"B34","doi-asserted-by":"publisher","first-page":"2126","DOI":"10.1038\/s41467-023-37568-9","article-title":"Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer","volume":"14","author":"Robertson","year":"2023","journal-title":"Nat Commun"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.clgc.2024.102214","article-title":"Distinct gene expression patterns identify patients who relapse after neoadjuvant pembrolizumab and radical cystectomy in the PURE-01 study","volume":"22","author":"Reike","year":"2024","journal-title":"Clin Genitourin Cancer"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0628-7","article-title":"Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial","volume":"25","author":"Powles","year":"2019","journal-title":"Nat Med"},{"key":"B37","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":"B38","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-24-0649","article-title":"Different PD-L1 assays reveal distinct immunobiology and clinical outcomes in urothelial cancer","volume":"13","author":"Galsky","year":"2025","journal-title":"Cancer Immunol Res"},{"key":"B39","doi-asserted-by":"publisher","first-page":"7995","DOI":"10.1038\/s41467-025-63309-1","article-title":"Clonal diversity shapes the tumour microenvironment leading to distinct immunotherapy responses in metastatic urothelial carcinoma","volume":"16","author":"Kamatani","year":"2025","journal-title":"Nat Commun"},{"key":"B40","doi-asserted-by":"publisher","first-page":"2098","DOI":"10.1016\/j.ccell.2024.10.016","article-title":"Molecular heterogeneity in urothelial carcinoma and determinants of clinical benefit to PD-L1 blockade","volume":"42","author":"Hamidi","year":"2024","journal-title":"Cancer Cell"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1979524\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T11:33:02Z","timestamp":1790335982000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1979524\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,25]]},"references-count":40,"alternative-id":["10.3389\/fimmu.2026.1979524"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1979524","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,25]]},"article-number":"1979524"}}