Aug 2026· Microbiology Research· Vol 313, pp.
128682
· 0 citations· 131 references
Medicine
TL;DR
This review highlights chassis selection, circuit architectures, applications for metabolic diseases and cancer, metabolic bottlenecks, and future directions for precision microbial therapeutics for metabolic disorders and oncology.
Abstract
Synthetic biology has redefined the therapeutic role of microbes, transforming them from passive commensals or delivery vehicles into programmable living therapeutics capable of sensing, computing, and actuating within host tissues. This transformation is particularly relevant to metabolic disorders and oncological conditions in which pathophysiology is spatially heterogeneous, dynamically regulated and strongly modulated by host-microbe interactions. Engineered bacterial strains and other microbial platforms can be designed to degrade toxic metabolites, replace deficient enzymes or hormones, alter bile-acid and short-chain-fatty-acid profiles, modulate host immunity, and deliver antitumor payloads with spatial precision. In metabolic disorders, early live biotherapeutic programs have demonstrated that engineered Escherichia coli is capable of metabolically degrading phenylalanine in phenylketonuria, thereby providing a clinical proof of mechanism for gut-restricted metabolic interception. In oncology, tumor colonizing bacteria have been engineered to express cytokines, checkpoint inhibitors, lytic toxins, and diagnostic signals, and their application has been recently demonstrated in colorectal cancer detection and localized immunomodulation. Despite this progress, clinical translation remains limited by variable survival and functional activity in vivo, inconsistent engraftment, metabolic and genetic instability, biocontainment requirements, manufacturing complexity, and uncertain dose control, persist in biogenetic engineering. This review highlights chassis selection, circuit architectures, applications for metabolic diseases and cancer, metabolic bottlenecks, and future directions for precision microbial therapeutics.
Engineered live biotherapeutic products (eLBPs) represent an emerging class of programmable microbial therapies capable of sensing and responding to host physiology. Advances in microbiome science and synthetic biology have driven the development of engineered bacteria that deliver therapeutic molecules, modulate host metabolism, or detect disease-associated signals. In this review, we summarize recent progress in the development of eLBPs across diverse disease indications, including inflammatory diseases, metabolic disorders, cancer, and infectious diseases. We highlight key factors that drive successful eLBP design, including chassis selection, methods for DNA delivery, approaches for tuning therapeutic expression, and genetic systems for biocontainment. Although early clinical studies demonstrate promising safety profiles, challenges remain in achieving predictable colonization, durable therapeutic activity, and robust biocontainment in vivo. By synthesizing advances across these areas, we propose a framework for the rational design of next-generation eLBPs that can more reliably translate from experimental systems to clinical application.
Elizabeth A. Brown, Arianna Brevi, D. Zong et al.· Cell Host and Microbe· 0 citations
Targeted cancer therapies increasingly require platforms that can penetrate poorly perfused tumor regions while minimizing systemic toxicity. Bacteria, owing to their intrinsic tumor tropism, genetic programmability, and immunostimulatory properties, have re-emerged as versatile anticancer agents, ranging from attenuated tumor-colonizing strains to highly engineered “living therapeutics.” In this review, we synthesize the mechanistic foundations and therapeutic advances of bacterial-based cancer therapy through four major themes. First, we examine foundational mechanisms, including tumor-selective colonization, direct oncolysis and cytotoxicity, activation of innate and adaptive immunity, and remodeling of the tumor microenvironment. Second, we discuss engineering strategies that enable controllable delivery of therapeutic payloads, such as cytokines, antibodies and nanobodies, enzyme-prodrug systems, toxins, and nucleic-acid therapeutics, while also improving biosafety and biocontainment. Third, we evaluate combination strategies integrating bacteria with chemotherapy, radiotherapy, phototherapy, and immunotherapy, with emphasis on how bacteria complement conventional modalities by targeting hypoxic, necrotic, and immunologically refractory tumor niches. Fourth, we summarize translational progress, including representative early-phase clinical experiences, manufacturing challenges, and major safety constraints. We also highlight emerging microbiome-disease databases and computational resources that may support target selection, biomarker discovery, and therapy-response stratification. Current evidence supports bacteria as a promising precision modality, particularly for immunologically “cold” or hypoxic tumors; however, major challenges remain in the predictability of intratumoral distribution, host clearance, genetic stability, and long-term safety. Addressing these barriers through rigorous engineering, standardized manufacturing, and clinically meaningful endpoints will be essential for the next generation of bacterial therapeutics in oncology.
Arman H. Sharifi, Ngoc Hai Trieu Phong, Anjali Marek et al.· Molecular Biomedicine· 0 citations
The dynamic interplay between intratumoral bacteria and cancer progression has unveiled new avenues for precision oncology, positioning bacteria as versatile, programmable platforms for targeted therapy. This review systematically explores the dual roles of tumor‐associated microbiota‐both promoting and suppressing malignancy‐and highlights the transformative potential of engineered bacterial systems in cancer treatment. Capitalizing on their innate tropism for hypoxic tumor cores, bacteria serve as self‐propelled, living drug carriers capable of localized delivery of cytotoxic agents, immunomodulators, and prodrug‐converting enzymes. Advances in synthetic biology and nano‐biohybrid designs have further enabled the development of intelligent bacterial vectors that respond to tumor‐specific signals, thereby minimizing off‐target effects and enhancing therapeutic precision. We discuss innovative strategies in which bacteria are harnessed to remodel the immunosuppressive tumor microenvironment (TME), potentiate immune checkpoint therapies, and synergize with conventional modalities such as chemotherapy, radiotherapy, and photodynamic therapy. Emphasis is placed on bacterial‐derived components‐including outer membrane vesicles, spores, and metabolites‐that can be functionally repurposed for cancer immunotherapy and targeted drug delivery. Furthermore, we examine ongoing clinical trials that underscore the translational feasibility of bacterial therapeutics, while also addressing persistent challenges in safety, biocontainment, and manufacturing scalability. Looking forward, we envision a new paradigm in which engineered bacteria, integrated with real‐time imaging and personalized microbiome profiling, evolve from experimental tools into clinically deployable “living medicines.” By bridging synthetic biology, immunology, and materials science, bacteria‐based platforms offer a promising frontier for achieving potent, specific, and adaptable cancer therapies.
Microbial cell therapies hold considerable promise as programmable and versatile modalities for targeted interventions in complex biological environments. Here, we developed a living bacterial delivery platform that could leverage its endogenous metabolism to synchronize the release of surface-anchored targeted protein degradation (TPD) chimeras and the secretion of immune-modulatory nanobodies (Nbs) for enhanced antitumor efficacy. By means of metabolic labeling coupled with bioorthogonal click chemistry, transferrin (Tf)-CD24 antibody chimeras (TransCACs) were covalently displayed on the surface of nonpathogenic Escherichia coli (E. coli) K12. In parallel, this strain was equipped with a constitutive expression module for the in situ biosynthesis of PD-L1-blocking nanobodies. Capitalizing on the natural tumor tropism of bacteria, our engineered E. coli K12 achieved tumor-targeted CD24 degradation, thereby augmenting macrophage-mediated phagocytosis and synergizing with PD-L1 blockade to elicit robust tumor-specific CD8+ T cell immunity. In vivo administration of engineered microbes led to marked tumor growth inhibition in both subcutaneous breast and orthotopic hepatocellular carcinoma models, along with prolonged animal survival, driven by remodeling of the suppressive tumor microenvironment through coordinated crosstalk between M1-like macrophages and tumor-resident memory (TRM)-like CD8+ T cells. Altogether, this integrated genetic engineering and metabolic labeling of bacteria (InGeM) opens avenues for the development of next-generation microbe-based cancer immunotherapies.
Xinping Hu, Yu Chen, Meiyuan Jin et al.· Journal of the American Chem...· 0 citations
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.
Jin-Hu Guo, Yimeng Li, Yueqi Yang et al.· Frontiers in Immunology· 0 citations
Microbial interventions are being developed as anticancer agents, local drug factories, replicating immunotherapies and modifiers of treatment response. Their appeal arises from properties that conventional medicines do not readily reproduce: active replication, environmental sensing, penetration of poorly perfused tissue, programmable payload production and the capacity to engage innate and adaptive immunity. This critical narrative review evaluates tumour-targeting bacteria, engineered bacterial therapeutics, oncolytic viruses and manipulation of the host microbiome from a molecular-biology perspective. Literature published from 1 January 1990 to 29 May 2026 was selected through a transparent search of PubMed/MEDLINE, reference chaining and bibliographic verification of article identity and Digital Object Identifiers. The evidence indicates that microbial therapies operate through partially shared molecular modules: selective localisation or replication, pattern-recognition receptor signalling, immunogenic cell injury, antigen release and cross-presentation, metabolic reprogramming, and spatially restricted expression of therapeutic cargo. Yet the maturity of evidence differs sharply across platforms. Bacillus Calmette–Guérin and talimogene laherparepvec demonstrate that live microbial products can achieve clinical utility, whereas most engineered bacteria remain supported mainly by murine models and early-phase studies. Oncolytic viruses have produced durable responses in selected settings, but apparently strong phase I or II signals have not always translated into improved survival in randomised trials. Gut-microbiome associations with immune-checkpoint inhibitor outcomes are reproducible at a broad ecological level but inconsistent at the level of individual taxa; early faecal microbiota transplantation studies provide proof of principle rather than definitive efficacy. Across platforms, the central translational problem is not simply potency but control: biodistribution, genetic stability, inflammatory dose, immune clearance, manufacturing consistency and reversibility must be treated as molecular design variables. Progress will depend on mechanism-linked biomarkers, standardised pharmacodynamic measurements, rational combination trials and containment architectures that are validated under clinically realistic conditions.
Ummulkhairi Tukur, Imran Yahaya Umar, Aminat Oyiza Musa et al.· Asian Journal of Research in...· 0 citations
