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

Ke Liu1,2,3, Xia Xue1,2,3, Haiming Qin4,5

  • 1Henan Key Laboratory for Helicobacter Pylori and Digestive Tract Microecology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, 450001, China.

Oncology Research
|January 30, 2026
PubMed
Abstract

Insights

Two gut metabolites, 16(R)-HETE and 6-Keto-PGE1, enhance PD-L1 expression and boost immunotherapy efficacy in prostate cancer (PC). Targeting the gut-tumor metabolic axis improves immune checkpoint inhibitors (ICIs) in PC.

Area of Science:

  • Oncology
  • Immunology
  • Metabolomics

Background:

  • The gut microbiome significantly influences cancer immunotherapy response.
  • Mechanisms linking gut metabolites to checkpoint blockade efficacy in prostate cancer (PC) are underexplored.
  • Immune checkpoint inhibitors (ICIs) are crucial in cancer treatment, but their efficacy varies.

Purpose of the Study:

  • To investigate how gut metabolites regulate programmed death-ligand 1 (PD-L1) blockade via exosomes.
  • To explore the role of gut metabolites in enhancing immune checkpoint inhibitors (ICIs) efficacy in PC.
  • To elucidate the gut-tumor metabolic axis in PC immunotherapy.

Main Methods:

  • Integrated multi-omics analysis of 70 PC patients across five subgroups.
  • In vitro validation in PC cell lines and in vivo studies using transgenic adenocarcinoma of the mouse prostate (TRAMP) models.
  • Assessment of PD-L1 expression and immunotherapy treatment efficacy.

Main Results:

  • Identified 16(R)-Hydroxyeicosatetraenoic acid (16(R)-HETE) and 6-Keto-Prostaglandin E1 (6-Keto-PGE1) correlating with plasma exosomal PD-L1.
  • Both metabolites enhanced PD-L1 expression at multiple levels (mRNA, protein, exosome) in human and mouse PC cells.
  • These metabolites significantly promoted anti-PD-L1 efficacy in PC models.

Conclusions:

  • Targeting the gut-tumor metabolic axis offers a promising strategy for improving ICI efficacy.
  • Gut metabolites play a direct role in modulating PD-L1 expression and immunotherapy response in PC.
  • Further research into the gut-tumor metabolic axis could lead to novel therapeutic approaches for PC.
Keywords:
Gut microbiomegut-tumor metabolic axisimmunotherapymetabolitesprogrammed death-ligand 1prostate cancer

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