PD-1/PD-L1 inhibitors have emerged as standard treatments for advanced solid tumors;however,challenges such as a low overall response rate and systemic side effects impede their implementation.Hypoxia drives the remod...PD-1/PD-L1 inhibitors have emerged as standard treatments for advanced solid tumors;however,challenges such as a low overall response rate and systemic side effects impede their implementation.Hypoxia drives the remodeling of the tumor microenvironment,which is a leading reason for the failure of immunotherapies.Despite some reported strategies to alleviate hypoxia,their individual limitations constrain further improvements.Herein,a novel two-pronged strategy is pre-sented to efficiently address hypoxia by simultaneously adopting atovaquone(ATO,inhibiting oxygen consumption)and oxyhemoglobin(HbO2,directly supplement-ing oxygen)within a multifunctional aggregate termed NPs-aPD-1/HbO2/ATO.In addition to eliminating hypoxia with these two components,this smart aggre-gate also includes albumin and an ROS-responsive cross-linker as a controlled release scaffold,along with PD-1 antibody(aPD-1)for immunotherapy.Intriguingly,NPs-aPD-1/HbO2/ATO demonstrates exceptional tumor targeting in vivo,exhibit-ing≈4.2 fold higher accumulation in tumors than in the liver.Consequently,this aggregate not only effectively mitigates hypoxia and significantly assists aPD-1 immunotherapy but also simultaneously resolves the targeting and systemic toxicity issues associated with individual administration of each component.This study pro-poses substantial implications for drug-targeted delivery,addressing tumor hypoxia and advancing immunotherapy,providing valuable insights for advancing cancer treatment strategies.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82073058,32371449)Basic Research Projects of the Natural Science Foundation of Shaanxi Province(key program)(2021JZ-37)+2 种基金Youth Cultivation Project of the First Affiliated Hospital of Xi’an Jiaotong University(No.2019QN-02)Nanjing Tianqing Research Fund Project(No.HX202324)the Clinical Research Award of the First Affiliated Hospital of Xi’an Jiaotong University,China(No.XJTU1AF-CRF-2022-009).
文摘PD-1/PD-L1 inhibitors have emerged as standard treatments for advanced solid tumors;however,challenges such as a low overall response rate and systemic side effects impede their implementation.Hypoxia drives the remodeling of the tumor microenvironment,which is a leading reason for the failure of immunotherapies.Despite some reported strategies to alleviate hypoxia,their individual limitations constrain further improvements.Herein,a novel two-pronged strategy is pre-sented to efficiently address hypoxia by simultaneously adopting atovaquone(ATO,inhibiting oxygen consumption)and oxyhemoglobin(HbO2,directly supplement-ing oxygen)within a multifunctional aggregate termed NPs-aPD-1/HbO2/ATO.In addition to eliminating hypoxia with these two components,this smart aggre-gate also includes albumin and an ROS-responsive cross-linker as a controlled release scaffold,along with PD-1 antibody(aPD-1)for immunotherapy.Intriguingly,NPs-aPD-1/HbO2/ATO demonstrates exceptional tumor targeting in vivo,exhibit-ing≈4.2 fold higher accumulation in tumors than in the liver.Consequently,this aggregate not only effectively mitigates hypoxia and significantly assists aPD-1 immunotherapy but also simultaneously resolves the targeting and systemic toxicity issues associated with individual administration of each component.This study pro-poses substantial implications for drug-targeted delivery,addressing tumor hypoxia and advancing immunotherapy,providing valuable insights for advancing cancer treatment strategies.
