Regulation of PD-1PD-L1 Immune Checkpoints by Gut Microbiota Metabolites and Their Clinical Translational Research: A Review.

BACKGROUND

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway have revolutionized cancer immunotherapy, yet their clinical benefit is constrained by variable response rates and immune-related adverse events.

AIMS: This review systematically analyzes the molecular mechanisms by which key gut microbiota-derived metabolites-including short-chain fatty acids (SCFAs), tryptophan metabolites, and bile acids-modulate the PD-1/PD-L1 axis.

MATERIALS &

METHODS

We synthesized and evaluated peer-reviewed preclinical and clinical studies published over the past decade, focusing on metabolite-immune interactions, biomarker validation, and combinatorial intervention strategies.

RESULTS

The summarized evidence demonstrates that these metabolites exert significant influences on the tumor microenvironment, enhance T-cell effector functions, and reshape immune tolerance, thereby affecting ICI responsiveness.

DISCUSSION: We critically assess the predictive value of microbiota metabolites as potential biomarkers and review current progress in probiotic supplementation, fecal microbiota transplantation, and metabolite-based combination therapies.

CONCLUSION

Despite promising translational prospects, several challenges-including inter-individual variability, lack of standardized protocols, and mechanistic gaps-remain to be addressed. Future directions should prioritize large-scale longitudinal studies and refined intervention designs to facilitate the clinical integration of microbiota-guided strategies, ultimately improving the precision and efficacy of cancer immunotherapy.