The microbiome as a systems-level regulator of immune, metabolic, neural, and endocrine signaling in cancer.

Cancer progression and therapeutic response remain highly variable across tumor types and are not fully explained by tumor-intrinsic alterations alone. The human microbiome has emerged as a systems-level regulator of cancer biology, integrating signals across immune, metabolic, neural, and endocrine axes. Microbial dysbiosis is associated with sustained inflammatory activation, genomic instability, and epigenetic reprogramming, linking microbial composition with tumor development. Microbiome-derived metabolites, including short-chain fatty acids (SCFAs), bile acids, and tryptophan derivatives, act as intermediates connecting microbial activity with host signaling networks that regulate immune cell function, metabolic pathways, neuroimmune communication, and hormonal balance. Convergence occurs through shared intracellular pathways, including NF-κB, STAT3, and WNT/β-catenin, shaping tumor initiation, progression, and therapeutic response. Microbiome-associated profiles have been proposed as diagnostic, prognostic, and predictive biomarkers, although clinical implementation remains limited by methodological variability, cohort heterogeneity, and lack of causal validation. The review integrates current evidence within a unified systems-level framework, defines mechanistic links between microbial functional outputs and host signaling pathways, and discusses microbiome-targeted strategies with relevance for precision oncology.