Abstract
Serum bile acids (BAs) emerge as risk factors for cancer, but their roles in colorectal cancer (CRC) remain unclear. We show that glycocholic acid (GCA), a primary BA, is elevated in the serum of CRC patients. In a mouse CRC model, GCA promotes tumor programmed death-ligand 1 (PD-L1) expression in tumors, suppressing CD8⁺ T cell-mediated antitumor immunity and facilitating tumor growth. Mechanistically, GCA inhibits the BA receptor farnesoid X receptor (FXR), a transcriptional repressor for SRY-box transcription factor 14 (SOX14). Loss of FXR repression upregulates SOX14-mediated expression of zinc finger DHHC-type palmitoyl transferase 9 (DHHC9), thereby reducing PD-L1 palmitoylation and stabilization. Silencing SOX14 or DHHC9, or activating FXR, synergizes with anti-PD-1 therapy, reducing tumor growth in GCA-treated mice. These findings uncover a mechanism that GCA remodels the tumor microenvironment to mediate CRC resistance to immunotherapy, highlighting therapeutic opportunities targeting the FXR-PD-L1 axis in CRC patients with elevated serum GCA.
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Data availability
The RNA sequencing data generated in this study have been deposited in the NCBI Gene Expression Omnibus (GEO) under the accession codes GSE241076 (RNA-seq, direct link: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE241076) and GSE241415 (scRNA-seq, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE241415). Metabolomics analysis of 33 bile acids (BAs) in serum samples from 20 healthy individuals and 80 CRC patients in cohort I was performed by Shanghai Applied Protein Technology Co., Ltd using mass spectrometry (MS)-based targeted metabolomics. The resulting metabolite concentration matrix, annotations, as well as transitions, retention times (in minutes), and quantity control data (RSD) are provided in Supplementary Data 1. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (https://proteomecentral.proteomexchange.org) via the iProX partner repository with the dataset identifier PXD075127. All data are available either in the main text or in the Supplementary Information upon request. Source data are provided with this paper.
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Acknowledgements
We thank OE Biotech Co., Ltd. (Shanghai, China) for providing single-cell RNA-seq and Dr. Xiaohua Yao and Wu Wang for assistance with bioinformatics analysis. The authors would like to acknowledge the following funding sources for supporting this work: National Nature Science Foundation of China (81972293, 82473078, DWL); National Nature Science Foundation of China (82003088, SLZ); National Nature Science Foundation of China (82273240, 82573187, PW); Shanghai Rising-Star Program (22QA1401800, SLZ); Program of Shanghai Academic/Technology Research Leader (22XD1420500, DWL); Intramural Research Program of NIH, NIDCR, USA (WJC).
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S.L.Z., J.Z., Y.S.M., B.Q., Z.J.H., and X.Y.Z. designed and performed experiments, analyzed data, and wrote the manuscript; Y.X., S.J.C., X.X.L., P.W., and W.J.C. provided critical scientific input; S.L.Z., Y.P.Z., J.Q.T., and D.W.L. conceived, initiated, supervised the whole study, and wrote the manuscript. All authors have approved the manuscript and agreed with the submission.
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Zhao, S., Zhang, J., Mi, Y. et al. Inhibition of circulating glycocholic acid-regulated signaling potentiates immune checkpoint therapy in colorectal cancer. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71403-1
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DOI: https://doi.org/10.1038/s41467-026-71403-1
