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ARTICLE

Gut Associated Metabolites Enhance PD-L1 Blockade Efficacy in Prostate Cancer

Ke Liu1,2,3,#, Xia Xue1,2,3,#, Haiming Qin4,5,#, Jiaying Zhu6,#, Meng Jin1,6, Die Dai6, Youcai Tang1, Ihtisham Bukhari1, Hangfan Liu1, Chunjing Qiu1, Feifei Ren1, Pengyuan Zheng1,2,3, Yang Mi1,2,3,*, Weihua Chen6,7,*
1 Henan Key Laboratory for Helicobacter Pylori and Digestive Tract Microecology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, 450001, China
2 Institute of Rehabilitation Medicine, Henan Academy of Innovations in Medical Science, Zhengzhou, 450001, China
3 Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou, 450001, China
4 Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450001, China
5 School of Public Health, Zhengzhou University, Zhengzhou, 450001, China
6 Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular-Imaging, Center for Artificial Intelligence Biology, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
7 School of Biological Science, Jining Medical University, Rizhao, 276800, China
* Corresponding Author: Yang Mi. Email: email; Weihua Chen. Email: email
# These authors contributed equally to this work
(This article belongs to the Special Issue: Advancing Cellular Therapeutics in Oncology: Innovations, Challenges, and Clinical Translation)

Oncology Research https://doi.org/10.32604/or.2025.072661

Received 01 September 2025; Accepted 10 December 2025; Published online 04 January 2026

Abstract

Background: The gut microbiome has emerged as a critical modulator of cancer immunotherapy response. However, the mechanisms by which gut-associated metabolites influence checkpoint blockade efficacy in prostate cancer (PC) remain not fully explored. The study aimed to explore how gut metabolites regulate death-ligand 1 (PD-L1) blockade via exosomes and boost immune checkpoint inhibitors (ICIs) in PC. Methods: We recruited 70 PC patients to set up into five subgroups. The integrated multi-omics analysis was performed. In parallel, we validated the function of gut microbiome-associated metabolites on PD-L1 production and immunotherapy treatment efficacy in PC cell lines and transgenic adenocarcinoma of the mouse prostate (TRAMP) models. Results: We identified two metabolites, 16(R)-Hydroxyeicosatetraenoic acid (16(R)-HETE) and 6-Keto-Prostaglandin E1 (6-Keto-PGE1), that positively correlated with the plasma exosomal PD-L1 levels. The in vitro experiments found that both 16(R)-HETE and 6-Keto-PGE1 can enhance PD-L1 expression at the mRNA, protein, and exosome levels in both human and mouse PC cell lines, which were also validated in vivo based on subcutaneous mouse models. Both metabolites significantly promoted the anti-PD-L1 efficacy against PC in situ on a TRAMP mouse model. Conclusions: Targeting the “gut-tumor metabolic axis” is a promising strategy to improve the efficacy of immune checkpoint inhibitors in tumors.

Keywords

Gut microbiome; metabolites; prostate cancer; programmed death-ligand 1; immunotherapy; gut-tumor metabolic axis

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