Programmable bacteria act as live biotherapeutics to remodel tumor stroma and potentiate immunotherapy

Abstract Immunotherapy has transformed cancer treatment but its efficacy is limited in many solid tumors in large part due to the immunosuppressive tumor microenvironment (TME). TME might be composed of a dense/stiff extracellular matrix (ECM) that impedes infiltration of immune cells. To address this abnormality, Neobe Therapeutics developed an engineered live biotherapeutic in the form of programmable bacteria that offer advantages for delivering enzymes to remodel the ECM. Using engineered Escherichia coli to express and release hyaluronidase under a hypoxia-inducible promoter, the bacteria target hyaluronan within the TME. Our study demonstrates that hyaluronan degradation reduces tumor stiffness and restores vascular functionality in murine models of breast cancer. This potentiates immune checkpoint inhibitor efficacy by facilitating immune cell infiltration and immunostimulation. Additionally, our findings suggest that the potency of antitumor responses depends on baseline stiffness levels and ECM composition, highlighting the potential of programmable bacteria to improve immunotherapy outcomes in drug resistant, solid tumors.