A tactical nanomissile mobilizing antitumor immunity enables neoadjuvant chemo-immunotherapy to minimize postsurgical tumor metastasis and recurrence

• Published in: Acta pharmaceutica Sinica. B Vol. 13; no. 2; pp. 804 - 818
• Main Authors: He, Tao, Hu, Mingxing, Zhu, Shunyao, Shen, Meiling, Kou, Xiaorong, Liang, Xiuqi, Li, Lu, Li, Xinchao, Zhang, Miaomiao, Wu, Qinjie, Gong, Changyang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-02-2023; Elsevier
• Subjects: Azobenzene derivatives; Chemotherapy; Immunotherapy; Melanoma; Mitoxantrone; Neoadjuvant; Original; Reduction responsive; Vaccine; Chemotherapy; Immunotherapy; Melanoma; Reduction responsive; Neoadjuvant; Vaccine; Mitoxantrone; Azobenzene derivatives
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2022.09.017

Neoadjuvant chemotherapy has become an indispensable weapon against high-risk resectable cancers, which benefits from tumor downstaging. However, the utility of chemotherapeutics alone as a neoadjuvant agent is incapable of generating durable therapeutic benefits to prevent postsurgical tumor metastasis and recurrence. Herein, a tactical nanomissile (TALE), equipped with a guidance system (PD-L1 monoclonal antibody), ammunition (mitoxantrone, Mit), and projectile bodies (tertiary amines modified azobenzene derivatives), is designed as a neoadjuvant chemo-immunotherapy setting, which aims at targeting tumor cells, and fast-releasing Mit owing to the intracellular azoreductase, thereby inducing immunogenic tumor cells death, and forming an in situ tumor vaccine containing damage-associated molecular patterns and multiple tumor antigen epitopes to mobilize the immune system. The formed in situ tumor vaccine can recruit and activate antigen-presenting cells, and ultimately increase the infiltration of CD8+ T cells while reversing the immunosuppression microenvironment. Moreover, this approach provokes a robust systemic immune response and immunological memory, as evidenced by preventing 83.3% of mice from postsurgical metastasis or recurrence in the B16–F10 tumor mouse model. Collectively, our results highlight the potential of TALE as a neoadjuvant chemo-immunotherapy paradigm that can not only debulk tumors but generate a long-term immunosurveillance to maximize the durable benefits of neoadjuvant chemotherapy.
A kind of reduction responsive tactical nanomissiles as neoadjuvant chemo-immunotherapy setting promoted the formation of in situ tumor vaccines and PD-1/PD-L1 pathway blockage, and successfully inhibited postoperative tumor recurrence and metastasis. [Display omitted]