The gut microbiome-immune-antioxidant axis: Redox-driven host-microbial crosstalk as a determinant of cancer immunotherapy response

Abstract

Introduction: The gut microbiome, host redox homeostasis, and immune regulation are mechanistically interdependent. However, their integrated role in driving resistance to immune checkpoint inhibitors remains incompletely defined.Objective: This review introduces the gut microbiome, immune, and antioxidant (GIA) axis as a unifying, systems-level conceptual framework to explain treatment heterogeneity and optimize cancer immunotherapy outcomes.Scope: We synthesize current mechanistic and translational evidence linking microbiota-derived metabolites, including short-chain fatty acids, bile acids, and tryptophan derivatives, to oxidative stress responses, mitochondrial fitness, and anti-tumor immune competence across colorectal, hepatobiliary, and neuro-oncologic malignancies.Key findings: Disruption of the GIA network promotes immunotherapy resistance through excessive oxidative burden, pathological Nrf2 signaling, and the expansion of immunosuppressive myeloid populations. Conversely, targeted microbiome interventions, including probiotics, postbiotics, and fecal microbiota transplantation, can successfully restore redox-immune equilibrium, remodel the tumor microenvironment, and enhance the efficacy of checkpoint blockade.Conclusion: We propose a precision immuno-oncology framework utilizing composite GIA-axis biomarker profiling for patient stratification. Integrating these multidisciplinary insights identifies actionable translational opportunities to overcome therapeutic resistance and transition host-microbiome-immune integration from conceptual promise to clinical reality.