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<p>Conventional type 1 dendritic cells (cDC1s) play a pivotal role in initiating CD8<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> T-cell axis.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月27日

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  • 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

摘要

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.