Microwave‐Responsive AlEu‐MOFs Potentiate NLRP3‐Mediated Pyroptosis via a “Triple Initiating” Tactic for Breast Cancer Microwave‐Immunotherapy

Abstract Microwave thermotherapy is favored in clinical practice for breast cancer conservation strategies due to its minimally invasive characteristic. Nevertheless, the immunosuppressive tumor microenvironment (TME) significantly attenuates the therapeutic efficacy of anti‐tumor immune response, posing challenges in effectively preventing tumor recurrence and metastasis. Pyroptosis, a recently identified form of programmed cell death triggered by inflammasomes, presents unique inflammatory and immunogenic properties that hold promise for cancer immunotherapy. Herein, microwave‐responsive AlEu‐MOFs are designed and synthesized to boost NLRP3‐mediated pyroptosis via a “Triple Initiating” tactic for breast cancer microwave‐immunotherapy. The potent microwave thermal effect of AEM facilitates the up‐regulation of HSP90, thereby initiating NLRP3 expression. Concurrently, it induces mitochondrial dysfunction to generate substantial quantities of ROS, further enhancing NLRP3 expression to achieve a targeted amplification of microwave thermotherapy‐induced pyroptosis. Simultaneously, the microwave‐responsive directed anchoring release of highly active metal ions promotes the activation of the NLRP3 inflammasome jointly, ultimately inducing high‐efficiency pyroptosis. This innovative “2M” (materials and methods) dual‐pronged strategy not only significantly inhibits primary tumor proliferation, but also further impedes distant tumor progression and lung metastasis. This work provides a novel strategy to accurately and effectively achieve pyroptosis and offers a new approach to overcome the obstacles of clinical microwave thermotherapy.