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