Targeting senescence with radioactive 223Ra/Ba SAzymes enables senolytics-unlocked One‐Two punch strategy to boost anti-tumor immunotherapy

Senescent cells are characterized by a persistent cessation of their cell cycle, rendering them valuable targets for anti-tumor strategies in cancer treatment. Numerous studies have explored induced senescence as a promising approach in tumor therapy. Nevertheless, these treatments often come with drawbacks, including adverse side effects and weaker senescence-inducing effects. To address these challenges, we synthesized ²²³Ra/Ba single-atom nanozyme (SAzyme), wherein Ba SAzyme acts concurrently as a carrier for ²²³RaCl₂, facilitating targeted delivery and minimizing side effects. The ²²³Ra/Ba SAzyme complex enhances various enzyme-mimicking functions, including catalase (CAT) and peroxidase (POD) activities. Importantly, ²²³Ra/Ba SAzyme induces cellular senescence and boost anti-tumor immunity. The persistent presence of a senescence-associated secretory phenotype (SASP) in the tumor microenvironment presents risks of immune suppression and tumor recurrence, which can be effectively mitigated by senolytics. As a result, ²²³Ra/Ba SAzyme were combined with anti-PD-L1 checkpoint blockade to achieve a one-two punch therapy, wherein ²²³Ra/Ba SAzyme exploits senescence followed by anti-PD-L1 therapy to eradicate senescent cells. This one‐two punch strategy approach presents a straightforward and potent intervention for both primary tumors and distant tumor.