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Synthetic Inducible Bacteria Normalize the Microenvironment of Refractory Tumors, Potentiating Checkpoint Inhibitor
Myrofora Panagi1, Fotios Mpekris2, Marcos Burger Ramos3
1Cancer Biophysics Laboratory, Department of Mechanical Engineering, University of Cyprus, Nicosia, Cyprus.
Molecular Cancer Therapeutics
|May 18, 2026
Summary
Engineered bacteria degrade tumor matrix hyaluronan, reducing stiffness and enhancing immunotherapy. This approach improves immune cell infiltration and activation, offering a novel strategy for solid tumor treatment.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Immunotherapy is limited in solid tumors by the immunosuppressive tumor microenvironment (TME).
- A dense extracellular matrix (ECM) impedes immune cell infiltration, reducing therapeutic efficacy.
- Novel strategies are needed to remodel the TME for improved cancer treatment outcomes.
Purpose of the Study:
- To develop a programmable bacterial platform for TME normalization.
- To investigate the efficacy of bacterial-mediated hyaluronan (HA) degradation in enhancing immunotherapy.
- To identify biomarkers predictive of therapeutic response in different cancer models.
Main Methods:
- Engineered nonpathogenic bacteria delivering hyaluronidase via tumor-inducible promoters.
- Assessment of TME normalization (stiffness, vascular function, immune infiltration) in murine breast and colorectal cancer models.
- Evaluation of immune checkpoint inhibitor efficacy and analysis of immune cell composition using machine learning.
Main Results:
- Bacterial hyaluronidase degraded HA, reducing tumor stiffness and restoring vascular function.
- Enhanced immune cell infiltration and activation led to improved immunotherapy efficacy in breast cancer models.
- Biomarker analysis revealed tumor-dependent response mechanisms, with stiffness and ECM composition critical in breast tumors, and immune cell composition in colorectal tumors.
Conclusions:
- Programmable bacteria represent a viable platform for TME modulation and enhanced cancer therapy.
- Targeting ECM components like HA can overcome physical barriers to immune cell infiltration.
- Understanding tumor-specific TME characteristics is crucial for optimizing immunotherapy strategies.
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