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.

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.

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.

Targeting the “gut-tumor metabolic axis” is a promising strategy to improve the efficacy of immune checkpoint inhibitors in tumors.