Abstract
Cancer immunotherapy resistance significantly challenges its clinical application. Traditional immunotherapy strategies are limited by the difficulty in delivering macromolecular immune modulators into the hypoxic core of tumors, leading to reduced efficacy and the development of resistance. Recently, bacterial-based delivery systems have been identified as a new approach in cancer therapy since bacteria have the potential of penetrating vascular barriers, infiltrating into deep tumor tissues and delivering therapeutics. To enhance the bio-safety and therapeutic efficiency, we developed an ultrasound-controlled, gene-engineered bacterial delivery system in which the bacteria are encapsulated in platelet-liposome hybrid membranes. Upon the application of low intensity focused ultrasound (LIFU), the engineered bacteria (Escherichia coli MG1655) can secrete melittin and granulocyte-macrophage colony-stimulating factor (GM-CSF) within the tumor regions. Melittin has a direct cytotoxic activity and also promotes the presentation of tumor-specific antigens, while GM-CSF reverses the immunosuppressive microenvironment and enhances antitumor immunity. This new strategy integrates bacterial therapeutics with sonogenetics, which provides the capability of achieving precise, controllable, and non-invasive killing of tumors. Based on our research, ultrasound-activated bacterial systems may be a new strategy for cancer immunotherapy.