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

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.