Engineered bacteria breach tumor physical barriers to enhance radio-immunotherapy

Radiotherapy widely applied for local tumor therapy in clinic has been recently reinvigorated by the discovery that radiotherapy could activate systematic antitumor immune response. Nonetheless, the endogenous radio-immune effect is still incapable of radical tumor elimination due to the prevention of immune cell infiltration by the physical barrier in tumor microenvironment (TME). Herein, an engineered Salmonella secreting nattokinase (VNP^NKase) is developed to synergistically modulate the physical and immune characteristics of TME to enhance radio-immunotherapy of colon tumors. The facultative anaerobic VNP^NKase enriches at the tumor site after systemic administration, continuously secreting abundant NKase to degrade fibronectin, dredge the extracellular matrix (ECM), and inactivate cancer-associated fibroblasts (CAFs). The VNP^NKase- dredged TME facilitates the infiltration of CD103⁺ dendritic cells (DCs) and thus the presentation of tumor-associated antigens (TAAs) after radiotherapy, recruiting sufficient CD8⁺ T lymphocytes to specifically eradicate localized tumors. Moreover, the pre-treatment of VNP^NKase before radiotherapy amplifies the abscopal effect and achieves a long-term immune memory effect, preventing the metastasis and recurrence of tumors. Our research suggests that this strategy using engineered bacteria to breach tumor physical barrier for promoting immune cell infiltration possesses great promise as a translational strategy to enhance the effectiveness of radio-immunotherapy in treating solid tumors.