Bile acids impedes tumor-specific T cell responses by modulating organelle-specific stress response 2754

The Journal of Immunology 2025

Siva Karthik Varanasi; Susan M. Kaech

Abstract

Abstract Description The metabolic landscape of cancer significantly influences anti-tumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We investigated the relationship between organ-specific metabolism and T cell responses in liver cancer. Accumulation of primary conjugated and secondary bile acids (BAs) were metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the bile acid-conjugating enzyme BAAT enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti-PD-1 immunotherapy. Furthermore, BAs regulated CD8+ T cells differently; primary BAs inhibited mitochondrial respiration and induced oxidative stress, whilst secondary BAs impaired T cell function through ER stress, which was countered by UDCA. Finally, therapeutic dietary supplementation of UDCA improved tumor-specific T cell responses and led to tumor control in multiple liver cancer model systems. Funding Sources P01 AG073084, R01 CA240909-04 and R21 AI151562 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

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