Dual-Pathway Pyroptosis Synergistically Triggered by ZIF-90 and Photothermal Boosting of Multienzyme Activity for Enhanced Breast Cancer Immunotherapy and Lung Metastasis Suppression

Immunotherapy is rapidly emerging as a potent, targeted therapy for breast cancer. However, the low immunogenicity and immunosuppressive tumor microenvironment (TME) in breast cancer limit its efficacy. In this study, a novel nanoreactor, CeO 2 :Mn (CM) embedded with the zeolitic imidazolate framework-90 (ZIF-90) and loaded with 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), is developed and designated CeO 2 :Mn/ZIF-90/ABTS (CMZA). Zn 2+ release from ZIF-90 degradation in the TME triggers pyroptosis and elevates intracellular •O 2 − levels by inhibiting the electron-transport chain. Furthermore, the CM nanozyme exhibits multienzyme activities, including superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), which convert •O 2 − to H 2 O 2 , generate •OH, produce O 2 , and oxidize ABTS to oxidized ABTS (oxABTS). The oxABTS exhibits strong near-infrared absorption and converts 808 nm light into heat, enhancing CM catalysis and depleting intracellular glutathione (GSH), thereby further amplifying the accumulation of reactive oxygen species (ROS). Collectively, CMZA induces NLRP3/c-Caspase-1/GSDMD-N pyroptosis through Zn 2+ release and photothermal-enhanced multienzyme activity, reshaping the TME and boosting immunogenicity to limit tumor progression and metastasis.