Aug 2026· Journal of the American Chemical Society· Vol 148 32, pp.
34393-34405
· 0 citations· 56 references
Medicine
TL;DR
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.
Abstract
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.
The clinical efficacy of melanoma immunotherapy is frequently compromised by an immunosuppressive, "cold" tumor microenvironment (TME) driven by redox dysregulation and the metabolic polarization of tumor-associated macrophages (TAMs). To overcome these intertwined barriers, a macrophage-targeted, biomimetic nanoplatform (MOF-808-Ro-G/N) is developed. This system integrates a catalytic metal-organic framework (MOF-808) core loaded with a PERK inhibitor and a CD47 blocking agent, encapsulated within a Rhizopus oryzae (Ro)-derived fungal shell. The biomimetic shell leverages Dectin-1 interactions to enable precise TAM targeting and accumulation. Upon endocytosis, the acidic endosomal microenvironment activates the MOF core to deplete glutathione and trigger a surge of reactive oxygen species, thereby inducing immunogenic cell death. Synergistically, the released payloads disrupt the PERK-ATF4 metabolic stress axis, reprogramming pro-tumorigenic M2 TAMs toward an anti-tumor M1 phenotype, while concurrently blocking the CD47-SIRPα checkpoint to restore macrophage phagocytosis. Through this orchestrated modulation, MOF-808-Ro-G/N effectively remodels the TME into an immunologically "hot" niche, promoting robust cytotoxic T lymphocyte infiltration and achieving substantial tumor growth suppression. Overall, this "metabolic-immune dual-reprogramming" strategy provides a promising materials-driven paradigm to overcome immunotherapy resistance in solid tumors.
Achieving tumor-specific delivery and sustained activation of both cytotoxic and immune-modulating agents remains a critical challenge in chemoimmunotherapy. Here, a bacterial platform was engineered to combine enzyme/prodrug chemotherapy with immunotherapy, in which tumor-homing Escherichia coli Nissle 1917 expressed cytosine deaminase to convert the prodrug 5-fluorocytosine into the cytotoxic drug 5-fluorouracil and concurrently produced an IL-15 superagonist and a PD-L1 blocking nanobody in tumors. This platform demonstrated potent antitumor effects in murine MC38 and B16-F10 solid tumor models. Mechanistic analyses showed that bacterial enzyme/prodrug therapy alone elicited both immune activation and compensatory immunosuppressive responses, whereas inclusion of IL-15 superagonist and PD-L1 blockade enhanced activation of antigen-presenting cells, T cells, and natural killer cells and attenuated immunosuppressive pathways. Abscopal and rechallenge experiments indicated that this bacterial chemoimmunotherapy strategy induces systemic antitumor immunity and durable immune memory. In summary, our approach integrates enzyme/prodrug therapy and immunotherapy into a single bacterial delivery system, overcoming key limitations of conventional therapies by providing a rationally designed framework for spatially controlled chemoimmunotherapy.
In BPAD, the potent and highly selective infection of OVs to tumor cells enhances both cellular uptake and tumor-selective delivery of PROTACs, resulting in a 640-fold increase in the protein degradation efficiency.
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.
B. Onoja, S. Agada, Waheeb S. Aggad et al.· Microbiology Research· 0 citations
A conceptual framework for harnessing living therapeutics to convert immunologically “cold” tumors into “hot”, therapy-sensitive lesions is provided and an AI-guided, microbiome-integrated framework to accelerate clinical translation is proposed.
Jin-Hui Guo, Yi-Meng Li, Yueqi Yang et al.· Frontiers in Immunology· 0 citations
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.
Arman H. Sharifi, Ngoc Hai Trieu Phong, Anjali Marek et al.· Molecular Biomedicine· 0 citations
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