A Dual‐Function Mitochondria‐Targeted Polyoxometalate Nanomicelle Boosts Pyroptosis‐Dependent Antitumor Immune Response in Triple‐Negative Breast Cancer

ABSTRACT The efficacy of immunotherapy in triple‐negative breast cancer (TNBC) is often limited, whereas the immunotherapeutic potential of pyroptosis is frequently undermined by a compensatory surge in mitophagy. To address this challenge, this study developed a reactive oxygen species (ROS)‐responsive and mitochondria‐targeted nanomicelle (POM@CTT). Upon encountering high ROS within mitochondria, POM@CTT could rapidly release the polyoxometalate (POM) component and generate singlet oxygen. Beyond inducing pyroptosis via the NLRP3/Caspase‐1/GSDMD axis, POM disrupted both the cellular and mitochondrial membranes based on the GSDMD N‐terminal fragment. This disruption further promoted mitochondrial DNA (mtDNA) release into the cytosol to activate the cGAS‐STING pathway. POM concurrently disrupted lysosomal function to block autophagic flux effectively. This blockade prevented pyroptosis‐induced compensatory mitophagy, which sustained and amplified the mtDNA‐cGAS‐STING axis‐mediated immune activation signal. In vivo, POM@CTT significantly promoted T‐cell infiltration into tumors. Its combined use with αPD‐L1 remarkably suppressed both primary and distant tumors and effectively prolonged the survival of tumor‐bearing mice. This study provides a novel strategy for overcoming TNBC immunotherapy resistance by inducing pyroptosis and blocking autophagic flux synergistically to remodel the tumor immune microenvironment.