Interplay between Gut Microbiome, Metabolites, and Tumor Immunity: Mechanisms and Clinical Translation

Gut microbiota-derived metabolites critically modulate the efficacy of tumor immunotherapy, particularly immune checkpoint inhibitors, by orchestrating key immunological mechanisms within the tumor immune microenvironment. Through multifaceted pathways, they dynamically regulate both innate and adaptive immunity or reshape tumor immunogenicity, thereby maintaining the delicate equilibrium between antitumor immune activation and suppression. Moreover, some microbial metabolites (e.g., butyrate, polyamines, succinic acid) have paradoxical or dual functions depending on the context (e.g., cancer type). A comprehensive understanding of the complex interplay among microbiota, metabolism, and immunity is important for clarifying individual variations in immunotherapeutic outcomes and may help inform strategies to overcome resistance. Current microbiota-based therapies, including probiotics, genetically engineered bacteria, and fecal microbiota transplantation, as well as interventions targeting metabolic pathways, are emerging as promising strategies to enhance immunotherapy by modulating host metabolic processes. However, several major challenges hinder clinical translation, including the bidirectional effects and concentration-dependent activity of metabolites, issues in delivery efficiency, and significant inter-individual heterogeneity. This review aims to systematically summarize the main mechanisms by which gut microbial metabolites regulate antitumor immunity and to explore the current landscape, strategies, and obstacles in their clinical application. Overall, it may provide a theoretical framework and practical perspectives for the future development of personalized tumor immunotherapies based on microbiome and metabolic interventions.