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...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.展开更多
Chemodynamic therapy(CDT),defined as an in situ oxidative stress response catalyzed by the Fenton or Fenton-like reactions to generate cytotoxic hydroxyl radicals(•OH)at tumor sites,exhibits conspicuous inhibition of ...Chemodynamic therapy(CDT),defined as an in situ oxidative stress response catalyzed by the Fenton or Fenton-like reactions to generate cytotoxic hydroxyl radicals(•OH)at tumor sites,exhibits conspicuous inhibition of tumor growth.It has attracted extensive attention for its outstanding edge in effectiveness,lower systemic toxicity and side effects,sustainability,low cost and convenience.However,the inconfor-mity of harsh Fenton reaction conditions and tumor microenvironment hamper its further development,based on which,numerous researchers have made efforts in further improving the efficiency of CDT.In this review,we expounded antitumor capacity of CDT in mechanism,together with its limitation,and then summarized and came up with several strategies to enhance CDT involved tumor therapy strategies by 1)improving catalytic efficiency;2)increasing hydrogen peroxide levels at tumor sites;3)reducing glutathione levels at tumor sites;4)applying external energy intervention;5)amplifying the distribu-tion of hydroxyl radicals at tumor sites;and 6)combination therapy.Eventually,the perspectives and challenges of CDT are further discussed to encourage more in-depth studies and rational reflections.展开更多
基金financially supported by the National Natural Science Foundation of China(82172094)Funds of Sichuan Province for Distinguished Young Scholar(2021JDJQ0037,China)1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYYC08002,China)。
文摘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.
基金supported by the National Natural Science Foundation of China(No.81822025)1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(No.ZYYC08002).
文摘Chemodynamic therapy(CDT),defined as an in situ oxidative stress response catalyzed by the Fenton or Fenton-like reactions to generate cytotoxic hydroxyl radicals(•OH)at tumor sites,exhibits conspicuous inhibition of tumor growth.It has attracted extensive attention for its outstanding edge in effectiveness,lower systemic toxicity and side effects,sustainability,low cost and convenience.However,the inconfor-mity of harsh Fenton reaction conditions and tumor microenvironment hamper its further development,based on which,numerous researchers have made efforts in further improving the efficiency of CDT.In this review,we expounded antitumor capacity of CDT in mechanism,together with its limitation,and then summarized and came up with several strategies to enhance CDT involved tumor therapy strategies by 1)improving catalytic efficiency;2)increasing hydrogen peroxide levels at tumor sites;3)reducing glutathione levels at tumor sites;4)applying external energy intervention;5)amplifying the distribu-tion of hydroxyl radicals at tumor sites;and 6)combination therapy.Eventually,the perspectives and challenges of CDT are further discussed to encourage more in-depth studies and rational reflections.
