Microbiome–Tumor–Host Interactions in Cancer Therapy: From Chemoresistance Mechanisms to Engineered Living Medicines

ABSTRACT This review synthesizes recent advances in pharmaco‐microbiomics, reframing cancer treatment in a hologenetic context, with host, tumor and microbiome acting as a tripartite entity. We comprehensively review microbiome‐mediated regulation of chemotherapeutic responses, encompassing both chemosensitization and resistance. At the molecular level, commensal microbiota enhance immunogenic cell death (ICD) and anti‐tumor immune responses, while intratumoral bacteria confer resistance through intracellular sequestration, induction of autophagy and drug inactivation (cytidine deaminase‐mediated gemcitabine degradation and β‐glucuronidase‐driven irinotecan toxicity). Our review also discusses systemic metabolic interactions including the “butyrate paradox”, competition for transporters, and microbiome‐mediated pharmacokinetics. Moving beyond microbiome profiling, we highlight functional metagenomics and resistome‐based patient stratification, complemented by AI‐based predictive modeling to predict non‐responders. In terms of translation, we outline next‐generation therapies such as engineered living medicines (ELMs), CRISPR‐bacteria for gene editing, precision bacteriophage therapy and postbiotic metabolites as precision approaches to reshape the tumor‐microbiome landscape. Finally, we present a clinical strategy combining microbiome companion diagnostics and co‐formulated “smart therapeutics” to combat multidrug resistance. This paradigm shift establishes microbiome as a predictor and therapeutic target in precision medicine.