Chenodeoxycholic acid restrains tumor growth via TGR5-dependent type 1 dendritic cells cross-priming.

Authors

Fanlian Zeng, Fulei Zhao, Pei Zhou, Ya Li, Xiaoyan Wang, Yawen Hu, Jiadong Yu, Guolin Li, Chengcheng Yue, Yuting Feng, Nongyu Huang, Xiaochi Sun, Xinmeng Wang, Shishi Huang, Mingxiang He, Wenling Wu, Kaijun Cui, Jiong Li

Published in

Signal transduction and targeted therapy. Volume 11. Issue 1. Jul 27, 2026. Epub Jul 27, 2026.

Abstract

Conventional type 1 dendritic cells (cDC1s) play a pivotal role in initiating CD8⁺ T-cell-mediated antitumor immunity, and their intratumoral abundance strongly correlates with immunotherapy efficacy. Here, we demonstrate that orally administered chenodeoxycholic acid (CDCA), a clinically approved metabolic modulator, accumulates in the tumor interstitial fluid (TIF) of tumor-bearing mice as its metabolite taurochenodeoxycholic acid (TCDCA), thereby potentiating the antitumor functions of cDC1s and CD8⁺ T cells through a gut microbiota-independent mechanism. Mechanistic studies revealed that CDCA mediates this immunomodulatory effect via TGR5 signaling, which enhances cDC1 functionality and subsequently promotes the proliferation and activation of tumor-specific CD8⁺ T cells. Clinical correlation analysis of human tumor specimens revealed a positive association between Takeda G protein-coupled receptor 5 (TGR5) expression and HLA-A/B/C/E/F/H levels, with elevated TGR5 expression significantly predicting improved overall patient survival. Moreover, CDCA exhibits synergistic antitumor effects when combined with anti-PD-1 immunotherapy and a poly I:C adjuvant, leading to robust tumor growth suppression and enhanced antitumor-immune responses. Overall, our study elucidates a novel immunoregulatory mechanism through which CDCA modulates tumor progression, highlighting CDCA and its bile acid derivatives as promising therapeutic candidates for cancer immunotherapy, providing a potential strategy to overcome resistance in cold tumors by revitalizing the cDC1-CD8⁺ T-cell axis.

PMID:
42503514
Bibliographic data and abstract were imported from PubMed on 27 Jul 2026.

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