The microbiota-m⁶A-metabolism axis: Implications for therapeutic strategies in gastrointestinal cancers

Gastrointestinal (GI) cancers remain a leading cause of cancer-related mortality worldwide, with metabolic reprogramming recognized as a central driver of tumor progression and therapeutic resistance. Among the key regulatory layers, N⁶-methyladenosine (m⁶A) RNA modification-mediated by methyltransferases (writers such as METTL3/14), RNA-binding proteins (readers like YTHDFs and IGF2BPs), and demethylases (erasers including FTO and ALKBH5), plays a pivotal role in controlling gene expression and metabolic flux in the tumor context. Concurrently, the gut microbiota profoundly influences GI tumorigenesis and immune evasion by modulating metabolite availability and remodeling the tumor microenvironment. Recent evidence has uncovered a bidirectional crosstalk between microbial metabolites and m⁶A methylation: microbiota-derived signals dynamically regulate m⁶A deposition on metabolic and immune transcripts, while m⁶A modifications, in turn, regulate the stability and translation of key mRNAs such as PD-L1 and FOXP3. This reciprocal interaction forms self-reinforcing epigenetic circuits that drive tumor plasticity, immune escape, and metabolic adaptation. In this review, we dissect the molecular underpinnings of the microbiota-m⁶A-metabolism axis in GI cancers and explore its potential to inform novel strategies in immunotherapy, metabolic intervention, and microbiome-guided precision oncology.