Gut Microbiota and nutrition as Emerging Modulators of Immune Checkpoint Inhibitor Therapy: Current Evidence, Challenges, and Future Perspectives.

Abstract

Immune checkpoint inhibitors (ICIs), a major class of cancer immunotherapies, have transformed the treatment of advanced cancers, yet durable benefit remains limited by primary or acquired resistance and immune-related adverse events (irAEs). Increasing evidence implicates the gut microbiome and nutritional state as modifiable host factors that may shape both therapeutic efficacy and toxicity. Here, we critically review the emerging evidence linking microbial ecology, dietary exposure, immunonutrition and ICI outcomes, with particular emphasis on the diet-microbiome-metabolite-immune axis. Clinical cohorts and preclinical models indicate that microbiome composition and, increasingly, microbial function and metabolic cross-talk are associated with ICI responsiveness, while microbiome perturbations may also influence susceptibility to irAEs. Dietary patterns and nutritional status likewise correlate with treatment outcomes, with dietary fibre and Mediterranean-style dietary patterns providing early clinical signals, whereas evidence for specific immunonutrients and restrictive dietary strategies remains inconsistent or insufficient. Mechanistically, dietary substrates can reshape microbial communities and metabolite production, thereby modulating immune-cell states and antitumour responses. However, these effects are highly context dependent and cannot be inferred from individual taxa or metabolites alone. We further examine emerging strategies that integrate nutritional optimization with microbiome modulation as a potential means of simultaneously improving efficacy and therapeutic tolerability. Despite substantial mechanistic progress, clinical evidence remains predominantly observational or early phase, and no microbiome-informed dietary intervention has yet established a reproducible benefit in prospective trials. Future studies should therefore move beyond descriptive associations towards evaluating causal, biomarker-guided and patient-stratified interventions integrating longitudinal dietary, microbiome, metabolomic and immune profiling.