Open Access

ARTICLE

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

Ke Liu^1,2,3,#, Xia Xue^1,2,3,#, Haiming Qin^4,5,#, Jiaying Zhu^6,#, Meng Jin^1,6, Die Dai⁶, Youcai Tang¹, Ihtisham Bukhari¹, Hangfan Liu¹, Chunjing Qiu¹, Feifei Ren¹, Pengyuan Zheng^1,2,3, Yang Mi^1,2,3,*, Weihua Chen^6,7,*

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 Authors: Yang Mi. Email: ; Weihua Chen. 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 2026, 34(2), 23 https://doi.org/10.32604/or.2025.072661

Received 01 September 2025; Accepted 10 December 2025; Issue published 19 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.

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Supplementary Material

Supplementary Material File

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