Intratumoral microbiota in cancer immunotherapy: metabolic-epigenetic crosstalk and engineered bacterial therapeutics

The intratumoral microbiome critically influences immunotherapy efficacy by modulating the host immune microenvironment and epigenetic landscape through its metabolites. Microbial derived metabolites such as short chain fatty acids, secondary bile acids, trimethylamine N oxide, and tryptophan derivatives reprogram host cell epigenetics via DNA methylation, histone modifications, and non-coding RNAs, thereby shaping anti-tumor immunity and driving either immune activation or resistance. In turn, the hypoxic, acidic, and nutrient deprived tumor microenvironment reshapes microbial composition and metabolism, forming a vicious cycle that further affects therapeutic outcomes. Given these pivotal roles, targeting the intratumoral microbiota has emerged as a promising strategy. Advances in synthetic biology have enabled the development of engineered bacteria as programmable living therapeutics. These engineered strains achieve tumor specific colonization, controlled drug release, and multimodal functions such as cytokine secretion, immune checkpoint blockade, STING pathway activation, and metabolic reprogramming. By enhancing immune checkpoint inhibitor efficacy and synergizing with cell therapies, engineered bacterial therapy represents a highly promising approach to improve immunotherapy efficiency. Despite challenges in clinical translation including heterogeneity, anti-vector immunity, and manufacturing complexity, this strategy offers a new paradigm for precision cancer treatment.