{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:15:52Z","timestamp":1789690552210,"version":"4.0.1"},"reference-count":74,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Folke Hermansen Foundation","award":["F-12320-D10192"],"award-info":[{"award-number":["F-12320-D10192"]}]},{"DOI":"10.13039\/501100004257","name":"Western Norway Regional Health Authority","doi-asserted-by":"publisher","award":["F-12593-D11698"],"award-info":[{"award-number":["F-12593-D11698"]}],"id":[{"id":"10.13039\/501100004257","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: High recurrence rates and intensive lifelong surveillance make bladder cancer among the costliest malignancies to treat. Although Bacillus Calmette\u2013Gu\u00e9rin (BCG) immunotherapy is the standard treatment for high-risk non-muscle-invasive bladder cancer (NMIBC), up to 50% of patients fail to respond, and predictive biomarkers are lacking. Molecular profiling has established three BCG response subtypes (BRS1\u20133), with BRS3 characterized by an immunosuppressive, BCG-resistant phenotype; however, these features have not been validated at single-cell spatial resolution. Methods: We applied imaging mass cytometry (IMC) to 82 BCG-treated high-risk NMIBC samples and performed (i) single-cell IMC with unsupervised clustering to identify phenotypic cell clusters and quantify cluster abundances and (ii) a convolutional neural network-based gated attention multiple instance learning model trained on IMC images (IMC-GA-MIL) to predict BCG response. Cluster abundances were summarized using II (immune composition within the immune compartment), TT (tumor phenotypic composition), and IT (immune\/stromal abundance relative to tumor cells) indices. Results: Single-cell IMC identified 18 distinct phenotypic cell clusters. In BCG responders, immune cells localized within the tumor compartment were enriched and independently protective (HR 0.67, 95% CI 0.49\u20130.92). BCG nonresponse was associated with a higher abundance of fibroblast-dominant clusters relative to tumor cells (IT index). Plasma cell-dominant clusters were the strongest predictors of progression (II index HR 2.28, 95% CI 1.37\u20133.79; IT index HR 1.25, 95% CI 1.06\u20131.48). The IMC-GA-MIL model predicted BCG response with 90% accuracy (9\/10) and identified myeloid- and T-cell-associated marker patterns involving CD14, CD11b, CD68, CD8, and FOXP3 as the most informative contributors. Conclusions: Spatial single-cell profiling and IMC-GA-MIL identify spatial immune and stromal features associated with BCG failure. However, findings from both analyses should be considered exploratory and will require validation in larger, independent cohorts.<\/jats:p>","DOI":"10.3390\/cancers18060938","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T09:26:38Z","timestamp":1773393998000},"page":"938","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Spatial Immune Profiling and AI-Based Classifiers Identify Predictors of BCG Therapy Outcomes in High-Risk Non-Muscle-Invasive Bladder Cancer"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8898-1330","authenticated-orcid":false,"given":"Melinda","family":"Lillesand","sequence":"first","affiliation":[{"name":"Department of Pathology, Stavanger University Hospital, 4011 Stavanger, Norway"},{"name":"Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, 4021 Stavanger, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Austdal","sequence":"additional","affiliation":[{"name":"Section for Biostatistics, Department of Research, Stavanger University Hospital, 4011 Stavanger, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakub","family":"Mroz","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering and Computer Science, University of Stavanger, 4021 Stavanger, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivar","family":"Skaland","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stavanger University Hospital, 4011 Stavanger, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Einar","family":"Gudlaugsson","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stavanger University Hospital, 4011 Stavanger, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6853-5982","authenticated-orcid":false,"given":"Florus C. de","family":"Jong","sequence":"additional","affiliation":[{"name":"Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tahlita C. M.","family":"Zuiverloon","sequence":"additional","affiliation":[{"name":"Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8970-0067","authenticated-orcid":false,"given":"Kjersti","family":"Engan","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering and Computer Science, University of Stavanger, 4021 Stavanger, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7760-5396","authenticated-orcid":false,"given":"Emiel A. M.","family":"Janssen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stavanger University Hospital, 4011 Stavanger, Norway"},{"name":"Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, 4021 Stavanger, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/s00345-009-0395-z","article-title":"Economic aspects of bladder cancer: What are the benefits and costs?","volume":"27","author":"Sievert","year":"2009","journal-title":"World J. Urol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Grabe-Heyne, K., Henne, C., Mariappan, P., Geiges, G., P\u00f6hlmann, J., and Pollock, R.F. (2023). Intermediate and high-risk non-muscle-invasive bladder cancer: An overview of epidemiology, burden, and unmet needs. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1170124"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3219","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":"ref_4","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.eururo.2024.07.027","article-title":"European Association of Urology guidelines on non\u2013muscle-invasive bladder cancer (TaT1 and carcinoma in situ)\u2014A summary of the 2024 guidelines update","volume":"86","author":"Gontero","year":"2024","journal-title":"Eur. Urol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.eururo.2016.05.041","article-title":"EAU guidelines on non\u2013muscle-invasive urothelial carcinoma of the bladder: Update 2016","volume":"71","author":"Babjuk","year":"2017","journal-title":"Eur. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"180","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":"ref_7","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.eururo.2019.08.016","article-title":"European association of urology guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ)-2019 update","volume":"76","author":"Babjuk","year":"2019","journal-title":"Eur. Urol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"eabn4118","DOI":"10.1126\/scitranslmed.abn4118","article-title":"Non\u2013muscle-invasive bladder cancer molecular subtypes predict differential response to intravesical Bacillus Calmette-Gu\u00e9rin","volume":"15","author":"Laajala","year":"2023","journal-title":"Sci. Transl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2796","DOI":"10.1016\/S0140-6736(16)30512-8","article-title":"Bladder cancer","volume":"388","author":"Kamat","year":"2016","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Lavallee, E., Sfakianos, J.P., and Mulholland, D.J. (2021). Tumor heterogeneity and consequences for bladder cancer treatment. Cancers, 13.","DOI":"10.3390\/cancers13215297"},{"key":"ref_11","first-page":"299","article-title":"Bacillus calmette-gu\u00e9rin (BCG) refractory non-muscle-invasive bladder cancer (NMIBC): Current guidance and experience from clinical practice","volume":"16","author":"Naselli","year":"2024","journal-title":"Res. Rep. Urol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Jiang, S., and Redelman-Sidi, G. (2022). BCG in bladder cancer immunotherapy. Cancers, 14.","DOI":"10.3390\/cancers14133073"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Leblond, M.M., Zdimerova, H., Desponds, E., and Verdeil, G. (2021). Tumor-associated macrophages in bladder cancer: Biological role, impact on therapeutic response and perspectives for immunotherapy. Cancers, 13.","DOI":"10.3390\/cancers13184712"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1172\/JCI59643","article-title":"Macrophage plasticity and polarization: In vivo veritas","volume":"122","author":"Sica","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Masucci, M.T., Minopoli, M., and Carriero, M.V. (2019). Tumor associated neutrophils. Their role in tumorigenesis, metastasis, prognosis and therapy. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.01146"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/1756-9966-32-87","article-title":"Tumor associated macrophages polarization dictates the efficacy of BCG instillation in non-muscle invasive urothelial bladder cancer","volume":"32","author":"Suriano","year":"2013","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Abou Chakra, M., Luo, Y., Duquesne, I., and O\u2019Donnell, M.A. (2024). Update on the mechanism of action of intravesical BCG therapy to treat non-muscle-invasive bladder cancer. Front. Biosci. (Landmark Ed.), 29.","DOI":"10.31083\/j.fbl2908295"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Miyake, M., Tatsumi, Y., Gotoh, D., Ohnishi, S., Owari, T., Iida, K., Ohnishi, K., Hori, S., Morizawa, Y., and Itami, Y. (2017). Regulatory T cells and tumor-associated macrophages in the tumor microenvironment in non-muscle invasive bladder cancer treated with intravesical Bacille Calmette-Gu\u00e9rin: A long-term follow-up study of a Japanese cohort. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102186"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Haist, M., Stege, H., Grabbe, S., and Bros, M. (2021). The functional crosstalk between myeloid-derived suppressor cells and regulatory T cells within the immunosuppressive tumor microenvironment. Cancers, 13.","DOI":"10.3390\/cancers13020210"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2916","DOI":"10.1172\/JCI89717","article-title":"ILC2-modulated T cell\u2013to-MDSC balance is associated with bladder cancer recurrence","volume":"127","author":"Chevalier","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s10875-012-9847-0","article-title":"Cancer-related inflammation","volume":"33","author":"Candido","year":"2013","journal-title":"J. Clin. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/s41416-022-02119-4","article-title":"Tumour-infiltrating lymphocytes: From prognosis to treatment selection","volume":"128","author":"Brummel","year":"2023","journal-title":"Br. J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Lim, C.J., Nguyen, P.H.D., Wasser, M., Kumar, P., Lee, Y.H., Nasir, N.J.M., Chua, C., Lai, L., Hazirah, S.N., and Loh, J.J.H. (2021). Immunological hallmarks for clinical response to BCG in bladder cancer. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.615091"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Joseph, M., and Enting, D. (2019). Immune responses in bladder cancer-role of immune cell populations, prognostic factors and therapeutic implications. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.01270"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"39916","DOI":"10.18632\/oncotarget.9537","article-title":"Tumor-infiltrating immune cell subpopulations influence the oncologic outcome after intravesical Bacillus Calmette-Gu\u00e9rin therapy in bladder cancer","volume":"7","author":"Pichler","year":"2016","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/s41585-018-0075-0","article-title":"BCG enriches Treg cells","volume":"15","author":"Fenner","year":"2018","journal-title":"Nat. Rev. Urol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zhang, Q., Zhang, W., Lin, T., Lu, W., He, X., Ding, Y., Chen, W., Diao, W., Ding, M., and Shen, P. (2022). Mass cytometry reveals immune atlas of urothelial carcinoma. BMC Cancer, 22.","DOI":"10.1186\/s12885-022-09788-7"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Shin, J., Park, J.W., Kim, S.Y., Lee, J.H., Choi, W.S., and Kim, H.S. (2024). Strategies for overcoming immune evasion in bladder cancer. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25063105"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.eururo.2022.09.008","article-title":"Elevated T-cell exhaustion and urinary tumor DNA levels are associated with BCG failure in patients with non-muscle invasive bladder cancer","volume":"82","author":"Strandgaard","year":"2022","journal-title":"Eur. Urol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1038\/s12276-023-01013-0","article-title":"Cancer-associated fibroblasts: From basic science to anticancer therapy","volume":"55","author":"Yang","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1016\/j.cell.2018.08.039","article-title":"A structured tumor-immune microenvironment in triple negative breast cancer revealed by multiplexed ion beam imaging","volume":"174","author":"Keren","year":"2018","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Khoraminia, F., Fuster, S., Kanwal, N., Olislagers, M., Engan, K., van Leenders, G.J., Stubbs, A.P., Akram, F., and Zuiverloon, T.C. (2023). Artificial intelligence in digital pathology for bladder cancer: Hype or hope? A systematic review. Cancers, 15.","DOI":"10.3390\/cancers15184518"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Feng, C., Wang, X., Tao, Y., Xie, Y., Lai, Z., Li, Z., Hu, J., Tang, S., Pan, L., and He, L. (2021). Single-cell proteomic analysis dissects the complexity of tumor microenvironment in muscle invasive bladder cancer. Cancers, 13.","DOI":"10.3390\/cancers13215440"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Feng, C., Wang, Y., Song, W., Liu, T., Mo, H., Liu, H., Wu, S., Qin, Z., Wang, Z., and Tao, Y. (2024). Spatially-resolved analyses of muscle invasive bladder cancer microenvironment unveil a distinct fibroblast cluster associated with prognosis. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1522582"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/s41586-019-1876-x","article-title":"The single-cell pathology landscape of breast cancer","volume":"578","author":"Jackson","year":"2020","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Fuster, S., Khoraminia, F., Silva-Rodr\u00edguez, J., Kiraz, U., van Leenders, G.J., Eftest\u00f8l, T., Naranjo, V., Janssen, E.A., Zuiverloon, T.C., and Engan, K. (2025). Self-contrastive weakly supervised learning framework for prognostic prediction using whole slide images. PLOS Digit. Health, 4.","DOI":"10.1371\/journal.pdig.0000972"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3565","DOI":"10.1038\/s41596-023-00881-0","article-title":"An end-to-end workflow for multiplexed image processing and analysis","volume":"18","author":"Windhager","year":"2023","journal-title":"Nat. Protoc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/s41587-021-01094-0","article-title":"Whole-cell segmentation of tissue images with human-level performance using large-scale data annotation and deep learning","volume":"40","author":"Greenwald","year":"2022","journal-title":"Nat. Biotechnol."},{"key":"ref_39","first-page":"10117","article-title":"Multi-modal image analysis for large scale cancer tissue studies within IMMUcan","volume":"5","author":"Eling","year":"2025","journal-title":"Cell Rep. Methods"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e31191","DOI":"10.1016\/j.heliyon.2024.e31191","article-title":"Development of a high dimensional imaging mass cytometry panel to investigate spatial organization of tissue microenvironment in formalin-fixed archival clinical tissues","volume":"10","author":"Tornaas","year":"2024","journal-title":"Heliyon"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1002\/cyto.a.24480","article-title":"Semi-automated background removal limits data loss and normalizes imaging mass cytometry data","volume":"99","author":"Ijsselsteijn","year":"2021","journal-title":"Cytometry A"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1038\/s41467-023-37123-6","article-title":"IMC-Denoise: A content aware denoising pipeline to enhance imaging mass cytometry","volume":"14","author":"Lu","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"107660","DOI":"10.1016\/j.cmpb.2023.107660","article-title":"ResNet and its application to medical image processing: Research progress and challenges","volume":"240","author":"Xu","year":"2023","journal-title":"Comput. Methods Programs Biomed."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"He, K., Zhang, X., Ren, S., and Sun, J. (2016, January 27\u201330). Deep Residual Learning for Image Recognition. Proceedings of the 2016 IEEE Conference on Computer Vision and Pattern Recognition (CVPR), Las Vegas, NV, USA.","DOI":"10.1109\/CVPR.2016.90"},{"key":"ref_45","unstructured":"Ilse, M., Tomczak, J., and Welling, M. (2018, January 10\u201315). Attention-Based Deep Multiple Instance Learning. Proceedings of the 35th International Conference on Machine Learning (ICML 2018), Stockholm, Sweden."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Kikuchi, M., Yoshida, M., Okabe, M., and Umemura, K. (2015, January 19\u201322). Confidence interval of probability estimator of Laplace smoothing. Proceedings of the 2015 2nd International Conference on Advanced Informatics: Concepts, Theory and Applications (ICAICTA 2015), Chonburi, Thailand.","DOI":"10.1109\/ICAICTA.2015.7335387"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.trecan.2023.03.006","article-title":"Spatial landscape of the tumor immune microenvironment","volume":"9","author":"Chen","year":"2023","journal-title":"Trends Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Liu, K., Liu, F., Li, G., and Zheng, Y. (2025). Multiplex imaging analysis of the tumor immune microenvironment for guiding precision immunotherapy. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1617906"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1016\/j.cell.2020.07.005","article-title":"Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front","volume":"182","author":"Bhate","year":"2020","journal-title":"Cell"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Seiffert, S., Weber, S., Sack, U., and Keller, T. (2024). Use of logit transformation within statistical analyses of experimental results obtained as proportions: Example of method validation experiments and EQA in flow cytometry. Front. Mol. Biosci., 11.","DOI":"10.3389\/fmolb.2024.1335174"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Manning, C., Raghavan, P., and Sch\u00fctze, H. (2008). Introduction to Information Retrieval, Cambridge University Press.","DOI":"10.1017\/CBO9780511809071"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1002\/pst.387","article-title":"A note on the Hodges\u2013Lehmann estimator","volume":"9","author":"Rosenkranz","year":"2010","journal-title":"Pharm. Stat."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1038\/modpathol.3800138","article-title":"Influence of breast cancer histology on the relationship between ultrasound and pathology tumor size measurements","volume":"17","author":"Pritt","year":"2004","journal-title":"Mod. Pathol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"36133","DOI":"10.1038\/s41598-025-21595-1","article-title":"Evaluating cell-specific gene expression using single-cell and single-nuclei RNA-sequencing data from human pancreatic islets of the same donors","volume":"15","author":"Nilsson","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1200\/JCO.2015.64.4070","article-title":"Definitions, end points, and clinical trial designs for non\u2013muscle-invasive bladder cancer: Recommendations from the International Bladder Cancer Group","volume":"34","author":"Kamat","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Huang, J., Lin, L., Mao, D., Hua, R., and Guan, F. (2024). Prognostic value of neutrophil-to-lymphocyte ratio in patients with non\u2013muscle-invasive bladder cancer with intravesical Bacillus Calmette\u2013Gu\u00e9rin immunotherapy: A systematic review and meta-analysis. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1464635"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1038\/s12276-024-01336-6","article-title":"VISTA-mediated immune evasion in cancer","volume":"56","author":"Zhang","year":"2024","journal-title":"Exp. Mol. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3113","DOI":"10.1007\/s00262-021-02906-7","article-title":"Expression of VISTA on tumor-infiltrating immune cells correlated with short intravesical recurrence in non-muscle-invasive bladder cancer","volume":"70","author":"Seo","year":"2021","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Pawar, J.S., Salam, M.A., Dipto, M.S.U., Al-Amin, M.Y., Salam, M.T., Sengupta, S., Kumari, S., Gujjari, L., and Yadagiri, G. (2025). Cancer-associated fibroblasts: Immunosuppressive crosstalk with tumor-infiltrating immune cells and implications for therapeutic resistance. Cancers, 17.","DOI":"10.3390\/cancers17152484"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4191","DOI":"10.1245\/s10434-019-07894-8","article-title":"Identification, friend or foe: Vimentin and \u03b1-smooth muscle actin in cancer-associated fibroblasts","volume":"26","author":"Nomura","year":"2019","journal-title":"Ann. Surg. Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Lee, H.H., and Al-Ogaili, Z. (2025). Fibroblast activation protein and the tumour microenvironment: Challenges and therapeutic opportunities. Oncol. Rev., 19.","DOI":"10.3389\/or.2025.1617487"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.euros.2024.06.011","article-title":"Fibroblast activation protein-\u03b1 and the immune landscape: Unraveling T1 non\u2013muscle-invasive bladder cancer progression","volume":"66","author":"Muilwijk","year":"2024","journal-title":"Eur. Urol. Open Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1186\/s12967-023-04151-1","article-title":"The potential crosstalk between tumor and plasma cells and its association with clinical outcome and immunotherapy response in bladder cancer","volume":"21","author":"Long","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e12830","DOI":"10.1111\/sji.12830","article-title":"Tumour-associated B cells in urothelial urinary bladder cancer","volume":"91","author":"Zirakzadeh","year":"2020","journal-title":"Scand. J. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.cmet.2017.10.006","article-title":"CD38\u2013NAD+ axis regulates immunotherapeutic anti-tumor T cell response","volume":"27","author":"Chatterjee","year":"2018","journal-title":"Cell Metab."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Morandi, F., Horenstein, A.L., and Malavasi, F. (2021). The key role of NAD+ in anti-tumor immune response: An update. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.658263"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1158\/2767-9764.CRC-24-0237","article-title":"A pilot study of the CD38 antagonist daratumumab in patients with metastatic renal cell carcinoma or muscle-invasive bladder cancer","volume":"4","author":"Campbell","year":"2024","journal-title":"Cancer Res. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.immuni.2019.02.002","article-title":"Adventitial stromal cells define group 2 innate lymphoid cell tissue niches","volume":"50","author":"Dahlgren","year":"2019","journal-title":"Immunity"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1016\/j.trecan.2023.06.010","article-title":"Perivascular niches: Critical hubs in cancer evolution","volume":"9","author":"Nowosad","year":"2023","journal-title":"Trends Cancer"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"461","DOI":"10.3389\/fimmu.2014.00461","article-title":"Toll-like receptor signaling pathways","volume":"5","author":"Kawasaki","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1093\/intimm\/dxn043","article-title":"Human Th1 differentiation induced by lipoarabinomannan\/lipomannan from Mycobacterium bovis BCG Tokyo-172","volume":"20","author":"Ito","year":"2008","journal-title":"Int. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"PR011","DOI":"10.1158\/1557-3265.BLADDER24-PR011","article-title":"Imaging mass cytometry captures patient heterogeneity enabling BCG response stratification in non-muscle invasive bladder cancer","volume":"30","author":"Pour","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.eururo.2024.01.023","article-title":"Prognostic impact and spatial interplay of immune cells in urothelial cancer","volume":"86","author":"Debatin","year":"2024","journal-title":"Eur. Urol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/j.eururo.2017.10.003","article-title":"Predicting response to intravesical bacillus Calmette-Gu\u00e9rin immunotherapy: Are we there yet? A systematic review","volume":"73","author":"Kamat","year":"2018","journal-title":"Eur. Urol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/6\/938\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T09:32:06Z","timestamp":1773394326000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/6\/938"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,13]]},"references-count":74,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["cancers18060938"],"URL":"https:\/\/doi.org\/10.3390\/cancers18060938","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,13]]}}}