Smart multi-functional aggregates reoxygenate tumor microenvironment through a two-pronged strategy to revitalize cancer immunotherapy

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 presented to efficiently address hypoxia by simultaneously adopting atovaquone (ATO, inhibiting oxygen consumption) and oxyhemoglobin (HbO₂, directly supplementing oxygen) within a multifunctional aggregate termed NPs-aPD-1/HbO₂/ATO. In addition to eliminating hypoxia with these two components, this smart aggregate 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, exhibiting ≈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 proposes substantial implications for drug-targeted delivery, addressing tumor hypoxia and advancing immunotherapy, providing valuable insights for advancing cancer treatment strategies.