Microbiota and tumor epigenetics: deep interconnections and emerging therapeutic perspectives

Cancer is a major global public health problem. Epigenetic regulation, such as DNA methylation, histone modifications, and non-coding RNA (ncRNA) dysregulation, is a main driver of tumorigenesis and progression. Recent studies are suggesting that the human microbiota, commonly referred to as a "super-organ," are not only associated with tumors but play an active role in regulating the epigenetic state of the host. The aim of this review is to systematically explain the main regulatory mechanisms of the "microbiota-epigenetic-cancer regulatory axis", their heterogeneous manifestations across various tumors, and the exploration of novel diagnostic biomarkers and therapeutic strategies of this regulatory axis. Microbiota mainly drive tumor epigenetic remodeling through three levels. First, microbial metabolites (e.g., butyrate) can act as natural histone deacetylase inhibitors (HDACis), or tryptophan metabolites can directly regulate the host chromatin state by activating the aryl hydrocarbon receptor (AhR) pathway. Second, bacterial structures such as lipopolysaccharide (LPS) can induce inflammation and disease by activating inflammatory signaling pathways. Third, specific pathogens like HBV and <i>Helicobacter pylori</i> can hijack the host's epigenetic machinery or induce epigenetic reprogramming via virulence factors. The tumor-resident microbiota (TRM) is an emerging and important field. TRM that actively partake in the tumor microenvironment (TME) may promote immune evasion through <i>in situ</i> mechanisms (e.g., lactylation), thereby confirming a direct and causal role for microbes within tumors. The epigenetic therapeutic strategies based on these mechanisms are being rapidly developed, including, for example, the regulation of microbial community structure (e.g., FMT), the targeting of microbial metabolic pathways, and TRM-specific approaches and key pathways (e.g., engineered bacteria). These strategies also have great potential as biomarkers for tumor prognosis prediction and therapy response evaluation. Overall, microbes and tumor epigenetics are part of a network that brings together their metabolism, inflammation, immunity, and gene regulation. Future research will shift from exploring the correlation of the gut microbiota at the macro level to exploring TRM's causality within the TME. By using gnotobiotic mouse models, organoid co-cultures, and multiomics, we will deeply analyze the microenvironment specificity of this network and develop precision interventions targeting TRM that could transform cancer therapy.