Hijacking tumor metabolism via sonocatalysis to orchestrate cuproptosis-pyroptosis coupling for potent antitumor...

In response to the high metabolic resilience and immunosuppression characteristic of triple-negative breast cancer, this study established a CuGaO₂ (CGO) nano sonocatalytic platform to reshape the therapeutic landscape through a metabolic hijacking dual death cascade strategy. The ultrasound activates CGO to generate reactive oxygen species (ROS), and facilitates the release of Cu⁺ and Ga³⁺ in tumor. The Ga³⁺ precisely disrupts iron metabolism and suppresses the expression of Fe-S cluster proteins via the metal mimicry effect, thereby achieving metabolic disarmament at a fundamental level. The decrease of Fe-S proteins, along with Cu⁺-induced dihydrolipoamide S-acetyltransferase (DLAT) oligomerization, results in dual protein toxicity, causing mitochondrial impairment and triggering efficient cuproptosis. ROS further directly damage mitochondria, leading to a reduction in ATP production. The consequent ion pump failure, coupled with oxidative stress, precisely triggers the caspase-1-mediated pyroptosis pathway. The inflammatory explosion interwoven with cuproptosis and pyroptosis, significantly amplifies cellular damage and promotes the release of immunogenic signals. In vivo results show that the system not only inhibits primary tumor growth, but also makes macrophages become a pro-inflammatory type, and increases CD8⁺ T cell infiltration, so it inhibits distant metastatic lesions. This cascade strategy offers a novel synergistic approach to overcoming metabolic resistance and metastasis in refractory tumors.