Programming the tumor microenvironment through microbiome-driven mechanisms

The tumor microenvironment (TME) comprises interacting immune, stromal, and metabolic compartments that determine tumor behavior and treatment response. Microbial communities modulate host signaling within the TME through metabolite-driven and receptor-mediated mechanisms. Lipopolysaccharides (LPS), short-chain fatty acids (SCFAs), bile acids, and amino acid–derived metabolites engage host receptors, including Toll-like receptors, G protein–coupled receptors, and aryl hydrocarbon receptor pathways, to regulate immune cell differentiation, antigen presentation, and metabolic adaptation. These microbiome-derived signals promote context-dependent immune suppression or immune activation according to metabolite concentration, receptor engagement, and immune cell composition, thereby influencing tumor progression and immune evasion. Host-driven inflammation and metabolic constraints reshape microbial composition and function within tumor-associated niches. Microbiome-associated mechanisms contribute to tumor initiation, progression, and therapeutic response through modulation of immune checkpoint activity and drug metabolism. Major limitations include reliance on associative human data, methodological variability across sequencing approaches, contamination in low-biomass samples, and incomplete integration of multi-omics datasets. Clinical translation requires mechanistic validation, longitudinal study designs, and standardized analytical frameworks to define reproducible microbiome-associated signatures.