Triple-negative breast cancer(TNBC)presents therapeutic challenges due to its aggressive,drug-resistance,and low immunological reactivity.Cuproptosis,an emerging therapeutic modality,is a promising strategic inter-ven...Triple-negative breast cancer(TNBC)presents therapeutic challenges due to its aggressive,drug-resistance,and low immunological reactivity.Cuproptosis,an emerging therapeutic modality,is a promising strategic inter-vention for treating TNBC.Nonetheless,the effectiveness of cuproptosis is compromised by tumor adaptations,including the Warburg effect,increased intracellular glutathione(GSH),and copper efflux,thus breaking the barrier of cuproptosis is the basis for developing cuproptosis-based clinical therapies.Herein,a self-accelerating strategy utilizing a pH-responsive copper framework encapsulating glucose oxidase(GOx),modified with polyethylene glycol(PEG)and tumor-penetrating peptide(tLyp1)has been developed.Upon reaching the acidic tumor microenvironment,the released GOx increases intracellular acidity and hydrogen peroxide(H_(2)O_(2)).The elevated intracellular GSH and H_(2)O_(2) serve as“fuel”to amplify the copper-based catalytic within tumor cells.Concurrently,the reduction of copper efflux proteins(ATP7B)and the depletion of GSH lead to copper overload in tumor cells,leading to cuproptosis via copper overload,mitochondrial disruption,and Fe-S protein instability.This constellation of interrelated events constitutes a potent“Copper Bomb,”which concurrently triggers the immune system and effectively kills the tumor.It robustly engages innate and adaptive immunity via the release of mitochondrial DNA,facilitating the cGAS-STING pathway and precipitating immunogenic cell death.This process reverses the immunosuppressive tumor microenvironment,eliminates tumor cells,and suppresses metastasis,thus offering a novel therapeutic modality for the comprehensive treatment of triple-negative breast cancer(TNBC).展开更多
基金supported by the China Postdoctoral Science Foundation,China(No.2023M740439)the Natural Science Foundation of Chongqing,China(CSTB2024NSCQ-MSX0894,CSTB2024NSCQMSX0460 and CSTB2022NSCQ-MSXC324)+2 种基金the Fundamental Research Funds for The Central Universities,China(No.2023CDJYGRH-ZD02)the Chongqing Science And Health Joint Medical Research Key Project,China(No.2025ZDXM015)the National Natural Science Foundation of China(No.82102225).
文摘Triple-negative breast cancer(TNBC)presents therapeutic challenges due to its aggressive,drug-resistance,and low immunological reactivity.Cuproptosis,an emerging therapeutic modality,is a promising strategic inter-vention for treating TNBC.Nonetheless,the effectiveness of cuproptosis is compromised by tumor adaptations,including the Warburg effect,increased intracellular glutathione(GSH),and copper efflux,thus breaking the barrier of cuproptosis is the basis for developing cuproptosis-based clinical therapies.Herein,a self-accelerating strategy utilizing a pH-responsive copper framework encapsulating glucose oxidase(GOx),modified with polyethylene glycol(PEG)and tumor-penetrating peptide(tLyp1)has been developed.Upon reaching the acidic tumor microenvironment,the released GOx increases intracellular acidity and hydrogen peroxide(H_(2)O_(2)).The elevated intracellular GSH and H_(2)O_(2) serve as“fuel”to amplify the copper-based catalytic within tumor cells.Concurrently,the reduction of copper efflux proteins(ATP7B)and the depletion of GSH lead to copper overload in tumor cells,leading to cuproptosis via copper overload,mitochondrial disruption,and Fe-S protein instability.This constellation of interrelated events constitutes a potent“Copper Bomb,”which concurrently triggers the immune system and effectively kills the tumor.It robustly engages innate and adaptive immunity via the release of mitochondrial DNA,facilitating the cGAS-STING pathway and precipitating immunogenic cell death.This process reverses the immunosuppressive tumor microenvironment,eliminates tumor cells,and suppresses metastasis,thus offering a novel therapeutic modality for the comprehensive treatment of triple-negative breast cancer(TNBC).
