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...

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Bibliographic Details
Published in:Journal of controlled release 2024-09, Vol.373, p.867-878
Main Authors: Zhang, Yanxiang, Liu, Yue, Li, Tingting, Yang, Xulu, Lang, Shanshan, Pei, Pei, Pei, Hailong, Chang, Lei, Hu, Lin, Liu, Teng, Yang, Kai
Format: Article
Language:English
Subjects:
CD103+ dendritic cells
Engineered bacteria
Radio-immunotherapy
Tumor microenvironment
Tumor physical barrier
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Summary: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 (VNPNKase) is developed to synergistically modulate the physical and immune characteristics of TME to enhance radio-immunotherapy of colon tumors. The facultative anaerobic VNPNKase 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 VNPNKase- 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 VNPNKase 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. Herein, VNP20009 is engineered to secrete NKase (VNPNKase), which modulates the physical and immune characteristics of solid tumors by degrading ECM and inactivating CAFs. VNPNKase-remodeled TME facilitates the tumoral infiltration of immune cells after radiotherapy, achieving complete elimination of primary tumors, a potent abscopal effect, and a long-term immune memory response, which is promising for promoting clinical radio-immunotherapy of solid tumors. [Display omitted] •VNP20009 is engineered to secret nattokinase (VNPNKase).•VNPNKase dredges the extracellular matrix and inactivates cancer-associated fibroblasts.•Tumor physical barrier breached by VNPNKase facilitates the tumoral infiltration of immune cells after radiotherapy.•VNPNKase-remodeled tumor microenvironment potentiates radio-immunotherapy of solid colon tumors.
ISSN:0168-3659
1873-4995
1873-4995
DOI:10.1016/j.jconrel.2024.07.076