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

Wenwen Zhang,Kailiang Zhou,Pinru Chen,Xuan-shuang Du,Min Liu

Published 2025 in Biology

ABSTRACT

Simple Summary Many people with early-stage bladder cancer receive bladder instillations of the tuberculosis vaccine strain, Bacillus Calmette–Guérin (BCG), yet many patients relapse. One reason is that cancer cells switch to high-rate glycolysis and release acid (lactate), which makes the body’s killer immune cells tired and less able to fight. We studied TIA1, an RNA-binding protein that forms liquid-like droplets (LLPS). We asked whether this droplet-forming ability links tumor glycolysis to CD8+ T-cell activity and BCG benefit. We found that people whose tumors had higher TIA1 were more likely to have better survival outcomes. In cells and mouse models, droplet competent TIA1 lowered glycolysis, reduced lactate, and increased CD8+ T-cell activation markers. BCG tended to enhance this pattern, and the effect depended on TIA1’s low-complexity domain. In our models, increased TIA1 expression was associated with slower tumor growth. Meanwhile, TIA1 binds glycolysis-related RNAs (LDHA, PKM2, and HK2), suggesting an mRNA-linked mechanism. Clinically, measuring TIA1 in tumor tissue may help identify patients more likely to benefit from BCG; for those with low TIA1, future strategies could consider metabolic or immune co-modulation to personalize treatment.

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