Molecular mechanisms of bacteria-mediated cancer immunotherapy: from intratumoral microbiota to engineered therapeutics
Immunotherapy has redefined oncology, yet its efficacy remains constrained by low response rates, primary or acquired resistance, immune-related toxicities, and escalating costs. Bacteria-mediated cancer immunotherapy (BCIT), which exploits the intratumoral microbiota as a programmable immunotherapeutic platform, has therefore emerged as a promising strategy. Although anecdotal links between infection and tumor regression were documented over four millennia ago, the molecular underpinnings of BCIT have only recently become accessible through synthetic biology, single-cell sequencing, and gnotobiotic modeling. Here we synthesize current knowledge on how intratumoral bacteria either enhance or suppress malignancy via genotoxicity, epigenetic reprogramming, metabolic competition, and modulation of the tumor-immune interface. We dissect cutting-edge engineering approaches—quorum-sensing circuits, thermo-inducible switches, molecular mimicry, and biohybrid microrobots, that convert commensal or attenuated pathogenic strains into precision delivery vehicles for cytokines, checkpoint inhibitors, and neoantigens. Finally, we critically evaluate translational bottlenecks (safety, pharmacokinetics, regulatory science, inter-patient heterogeneity) and propose an AI-guided, microbiome-integrated framework to accelerate clinical translation. This Review provides a conceptual framework for harnessing living therapeutics to convert immunologically “cold” tumors into “hot”, therapy-sensitive lesions, and discusses key directions for future microbiome-driven oncology trials.