Phase Separation Competent TIA1 Couples Glycolytic Shutdown to CD8+ T-Cell Activation and Shapes the Efficacy of Intravesical BCG in Bladder Cancer.

Metabolic immune evasion is a major factor limiting the long-term efficacy of intravesical Bacillus Calmette-Guérin (BCG) therapy in non-muscle-invasive bladder cancer (NMIBC). TIA1 is a stress granule RNA-binding protein with liquid-liquid 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 ΔLCD (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-immune 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.