{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T14:27:50Z","timestamp":1776349670337,"version":"3.51.2"},"reference-count":46,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T00:00:00Z","timestamp":1762819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China grants","doi-asserted-by":"crossref","award":["82272978"],"award-info":[{"award-number":["82272978"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Natural Science Foundation Project of Hubei Province","award":["2021CFB484"],"award-info":[{"award-number":["2021CFB484"]}]},{"name":"Open Foundation of Hubei Province Key Laboratory of Tumor Microenvironment and Immunotherapy","award":["2024KZL07"],"award-info":[{"award-number":["2024KZL07"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Metabolic immune evasion is a major factor limiting the long-term efficacy of intravesical Bacillus Calmette\u2013Gu\u00e9rin (BCG) therapy in non-muscle-invasive bladder cancer (NMIBC). TIA1 is a stress granule RNA-binding protein with liquid\u2013liquid phase separation (LLPS) capacity. Its role in tumor metabolism and immunotherapy response has been unclear. Here, we demonstrated that high TIA1 expression was independently associated with favorable survival across multiple cohorts. Full-length TIA1 formed cytoplasmic condensates, repressed LDHA\/PKM2\/HK2, reduced lactate, and lowered extracellular acidification. A condensate-defective \u0394LCD (deletion of the low-complexity domain) mutant was inactive. TIA1 showed physical association with these glycolytic mRNAs in human cells, consistent with mRNA-linked control. Condensate-competent TIA1 promoted CD8+ T-cell proliferation, increased CD69 and Granzyme-B, and reduced PD-1 in co-culture. TIMER (Tumor Immune Estimation Resource) and spatial-omics supported co-localization with tumoral CD8A. BCG induced this metabolic\u2013immune signature in cell lines, murine models, and patient explants, but the effects were abolished by TIA1 knock-down. Conversely, TIA1 over-expression alone limited tumor growth and recapitulated BCG-mediated glycolytic restraint and T-cell activation. Together, these results support an LLPS-linked, mRNA-associated regulation of tumor glycolysis. BCG-driven glycolytic suppression and CD8+ T cell activation track with the condensate-forming capacity of TIA1. TIA1 emerges as a prognostic biomarker and a potential therapeutic axis to improve intravesical immunotherapy in NMIBC.<\/jats:p>","DOI":"10.3390\/biology14111576","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T10:56:27Z","timestamp":1762858587000},"page":"1576","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Phase Separation Competent TIA1 Couples Glycolytic Shutdown to CD8+ T-Cell Activation and Shapes the Efficacy of Intravesical BCG in Bladder Cancer"],"prefix":"10.3390","volume":"14","author":[{"given":"Wenwen","family":"Zhang","sequence":"first","affiliation":[{"name":"Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kailiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"The Eighth Hospital of Wuhan, Wuhan 430010, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pinru","family":"Chen","sequence":"additional","affiliation":[{"name":"Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuanshuang","family":"Du","sequence":"additional","affiliation":[{"name":"Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7095-1344","authenticated-orcid":false,"given":"Min","family":"Liu","sequence":"additional","affiliation":[{"name":"Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Jian, N., Yu, L., Ma, L., Zheng, B., and Huang, W. (2025). BCG therapy in bladder cancer and its tumor microenvironment interactions. Clin. Microbiol. Rev., 38.","DOI":"10.1128\/cmr.00212-24"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Liatsos, G.D., Mariolis, I., Hadziyannis, E., Bamias, A., and Vassilopoulos, D. (2025). Review of BCG immunotherapy for bladder cancer. Clin. Microbiol. Rev., 38.","DOI":"10.1128\/cmr.00194-23"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e076743","DOI":"10.1136\/bmj-2023-076743","article-title":"Advances in diagnosis and treatment of bladder cancer","volume":"384","author":"Cookson","year":"2024","journal-title":"BMJ"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/j.eururo.2024.09.025","article-title":"Navigating the Challenges of BCG-Unresponsive Non-muscle-invasive Bladder Cancer: Insights and Future Directions","volume":"86","author":"Shariat","year":"2024","journal-title":"Eur. Urol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e145666","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. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1053\/j.gastro.2025.02.036","article-title":"Perforin Generated by CD8(+) T Cells Exacerbates Inflammatory Bowel Disease-Induced Depression by Promoting CXCL9 Production in Intestinal Epithelial Cells","volume":"169","author":"Huang","year":"2025","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.eururo.2022.08.004","article-title":"First-in-human Intravesical Delivery of Pembrolizumab Identifies Immune Activation in Bladder Cancer Unresponsive to Bacillus Calmette-Gu\u00e9rin","volume":"82","author":"Meghani","year":"2022","journal-title":"Eur. Urol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jiang, C., Zhou, Z., Shu, G., Yin, G., and Wang, M. (2025). Over-Expression of TNFRSF12A Promotes Immune Suppression and Facilitates Angiogenesis in Triple-Negative Breast Cancer. Biology, 14.","DOI":"10.3390\/biology14111513"},{"key":"ref_9","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 Bacillus Calmette-Gu\u00e9rin Failure in Patients with Non-muscle-invasive Bladder Cancer","volume":"82","author":"Strandgaard","year":"2022","journal-title":"Eur. Urol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e2","DOI":"10.1016\/S1473-3099(21)00403-5","article-title":"100 years of Mycobacterium bovis bacille Calmette-Gu\u00e9rin","volume":"22","author":"Lange","year":"2022","journal-title":"Lancet Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1080\/15548627.2024.2319512","article-title":"ATG5-regulated CCL2\/MCP-1 production in myeloid cells selectively modulates anti-malarial CD4(+) Th1 responses","volume":"20","author":"Gao","year":"2024","journal-title":"Autophagy"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Chen, Y., Sun, Y., and Liu, X. (2025). Identification of lactylation-associated immune and metabolic regulators in bladder cancer via integrated bulk and single-cell transcriptomics. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1604758"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zhi, H., Yin, W., Chen, S., Zhang, X., Yang, Z., Man, F., Li, R., Cai, Y., Li, Y., and You, C. (2026). Lactate metabolism regulating nanosystem synergizes cuproptosis and ferroptosis to enhance cancer immunotherapy. Biomaterials, 325.","DOI":"10.1016\/j.biomaterials.2025.123538"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"101197","DOI":"10.1016\/j.drup.2024.101197","article-title":"N6-methyladenosine modification of 3\u2019tRF-AlaAGC impairs PD-1 blockade efficacy by promoting lactic acid accumulation in the tumor microenvironment of gastric carcinoma","volume":"79","author":"Xu","year":"2025","journal-title":"Drug Resist. Updat."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e01238","DOI":"10.1002\/advs.202501238","article-title":"NDRG1-Driven Lactate Accumulation Promotes Lung Adenocarcinoma Progression Through the Induction of an Immunosuppressive Microenvironment","volume":"12","author":"Wu","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5997","DOI":"10.1038\/s41467-025-61112-6","article-title":"Small-molecule-induced liquid-liquid phase separation suppresses the carcinogenesis of \u03b2-catenin","volume":"16","author":"Yan","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"24113","DOI":"10.1021\/jacs.5c08019","article-title":"De Novo Peptides That Induce the Liquid-Liquid Phase Separation of \u03b1-Synuclein","volume":"147","author":"Ikenoue","year":"2025","journal-title":"J. Am. Chem. Soc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/s41392-022-01076-x","article-title":"Liquid-liquid phase separation in tumor biology","volume":"7","author":"Tong","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.it.2024.04.009","article-title":"Liquid-liquid phase separation in innate immunity","volume":"45","author":"Liu","year":"2024","journal-title":"Trends Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4628","DOI":"10.1038\/s41467-025-59759-2","article-title":"LLPS REDIFINE allows the biophysical characterization of multicomponent condensates without tags or labels","volume":"16","author":"Novakovic","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e2420399","DOI":"10.1002\/adma.202420399","article-title":"In Situ Liquid-Liquid Phase Separation of Peptides Into Droplets Targeting Membraneless Organelles for Enhanced Cancer Chemotherapy","volume":"37","author":"Wang","year":"2025","journal-title":"Adv. Mater."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5951","DOI":"10.1016\/j.cell.2024.08.018","article-title":"Biomolecular condensates regulate cellular electrochemical equilibria","volume":"187","author":"Dai","year":"2024","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7308","DOI":"10.1038\/s41467-025-62619-8","article-title":"PABPC1 SUMOylation enhances cell survival by promoting mitophagy through stabilizing U-rich mRNAs within stress granules","volume":"16","author":"Huang","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e70153","DOI":"10.1002\/jev2.70153","article-title":"Cancer Cell-Secreted miR-33a Reduces Stress Granule Formation by Targeting Polyamine Metabolism in Stroma to Promote Tumourigenesis","volume":"14","author":"Hu","year":"2025","journal-title":"J. Extracell. Vesicles"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1038\/s41589-025-01979-0","article-title":"Dissolving stress granules","volume":"21","author":"Dubinski","year":"2025","journal-title":"Nat. Chem. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wei, Y., Li, D., Yang, R., Liu, Y., Luo, X., Zhao, W., Yang, H., Chen, Z., Shen, C., and Wang, Y. (2025). TIA1-mediated stress granules promote neurodegeneration by sequestering HSP70 mRNA in C9orf72 mice. Brain, awaf248.","DOI":"10.1093\/brain\/awaf248"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e2409086","DOI":"10.1002\/advs.202409086","article-title":"TIA1-Mediated Stress Granules Promote the Neuroinflammation and Demyelination in Experimental Autoimmune Encephalomyelitis through Upregulating IL-31RA Signaling","volume":"12","author":"Hua","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"147589","DOI":"10.1016\/j.brainres.2021.147589","article-title":"Disease-associated mutations affect TIA1 phase separation and aggregation in a proline-dependent manner","volume":"1768","author":"Ding","year":"2021","journal-title":"Brain Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"West, D.L., Loughlin, F.E., Rivero-Rodr\u00edguez, F., Vankadari, N., Vel\u00e1zquez-Cruz, A., Corrales-Guerrero, L., D\u00edaz-Moreno, I., and Wilce, J.A. (2022). Regulation of TIA-1 Condensates: Zn(2+) and RGG Motifs Promote Nucleic Acid Driven LLPS and Inhibit Irreversible Aggregation. Front. Mol. Biosci., 9.","DOI":"10.3389\/fmolb.2022.960806"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.humpath.2024.07.002","article-title":"DUSP22-rearranged primary cutaneous CD30-positive T-cell lymphoproliferative disorders and adult T-cell leukemia\/lymphoma frequently share the LEF1+\/TIA1- immunophenotype","volume":"150","author":"Chen","year":"2024","journal-title":"Hum. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9","DOI":"10.14715\/cmb\/2023.69.14.2","article-title":"RAMP2-AS1 stabilized RAPM2 mRNA through TIA1 to inhibit the progression of non-small cell lung cancer","volume":"69","author":"Wang","year":"2023","journal-title":"Cell. Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Li, J., Ren, T., Liu, R., Zhang, H., Wang, N., Guo, Q., Xu, L., and Ma, J. (2025). Orbital natural killer\/T-cell lymphoma: A comprehensive case series and literature review. BMC Cancer, 25.","DOI":"10.1186\/s12885-025-13761-5"},{"key":"ref_33","first-page":"5592","article-title":"Significance of liquid-liquid phase separation (LLPS)-related genes in breast cancer: A multi-omics analysis","volume":"15","author":"Xie","year":"2023","journal-title":"Aging"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Wang, J., Meng, F., and Mao, F. (2022). Single cell sequencing analysis and transcriptome analysis constructed the liquid-liquid phase separation(LLPS)-related prognostic model for endometrial cancer. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1005472"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Zhang, L., Gao, H., Ma, S., Fan, X., Guo, H., Sun, M., Wen, S., Liu, T., Yu, G., and Yuan, X. (2025). Functional screening of somatic mutant events in extranodal natural killer\/T-cell lymphoma with adrenal involvement. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1566794"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.urolonc.2023.10.004","article-title":"Optimizing outcomes for high-risk, non-muscle-invasive bladder cancer: The evolving role of PD-(L)1 inhibition","volume":"41","author":"Bedke","year":"2023","journal-title":"Urol. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Jia, Q., Masle\u0161a-Gali\u0107, S., Nava, S., and Horwitz, M.A. (2022). Listeria-Vectored Multiantigenic Tuberculosis Vaccine Enhances Protective Immunity against Aerosol Challenge with Virulent Mycobacterium tuberculosis in BCG-Immunized C57BL\/6 and BALB\/c Mice. mBio, 13.","DOI":"10.1128\/mbio.00687-22"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3822","DOI":"10.1111\/cas.15047","article-title":"The Warburg effect as a therapeutic target for bladder cancers and intratumoral heterogeneity in associated molecular targets","volume":"112","author":"Burns","year":"2021","journal-title":"Cancer Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"eabf6548","DOI":"10.1126\/science.abf6548","article-title":"Ubiquitination of G3BP1 mediates stress granule disassembly in a context-specific manner","volume":"372","author":"Gwon","year":"2021","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.molcel.2024.11.012","article-title":"G3BP1 promotes intermolecular RNA-RNA interactions during RNA condensation","volume":"85","author":"Parker","year":"2025","journal-title":"Mol. Cell"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Sobolewski, C., Dubuquoy, L., and Legrand, N. (2022). MicroRNAs, Tristetraprolin Family Members and HuR: A Complex Interplay Controlling Cancer-Related Processes. Cancers, 14.","DOI":"10.3390\/cancers14143516"},{"key":"ref_42","first-page":"2823","article-title":"HuR, TTP, and miR-133b expression in NSCLC and their association with prognosis","volume":"25","author":"Qian","year":"2021","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1038\/s41467-021-21963-1","article-title":"Profiling PRMT methylome reveals roles of hnRNPA1 arginine methylation in RNA splicing and cell growth","volume":"12","author":"Li","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"113401","DOI":"10.1016\/j.celrep.2023.113401","article-title":"hnRNPA1 SUMOylation promotes cold hypersensitivity in chronic inflammatory pain by stabilizing TRPA1 mRNA","volume":"42","author":"Zhang","year":"2023","journal-title":"Cell Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.tibs.2019.07.004","article-title":"Metabolite Repair Enzymes Control Metabolic Damage in Glycolysis","volume":"45","author":"Bommer","year":"2020","journal-title":"Trends Biochem. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e202302396","DOI":"10.26508\/lsa.202302396","article-title":"Trafficking of mitochondrial double-stranded RNA from mitochondria to the cytosol","volume":"7","author":"Krieger","year":"2024","journal-title":"Life Sci. Alliance"}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/14\/11\/1576\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T12:17:23Z","timestamp":1763122643000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/14\/11\/1576"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,11]]},"references-count":46,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["biology14111576"],"URL":"https:\/\/doi.org\/10.3390\/biology14111576","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,11]]}}}