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<p>Despite advances in immunotherapy, triple-negative breast cancer (TNBC) remains a major therapeutic challenge owing to its marked aggressiveness, low immunogenicity, and limited responsiveness to immune checkpoint blockade (ICB). Herein, the esterase-responsive polymeric nanoparticles (EsCu@NPs) are developed. The polymer backbone covalently integrates an L-buthionine sulfoximine prodrug to inhibit glutathione biosynthesis, and the nanoparticle matrix encapsulates an elesclomol-copper complex to promote intratumoral copper accumulation. By concurrently depleting glutathione and perturbing copper homeostasis, EsCu@NPs elicit reinforced cuproptosis stress that is converted into immunogenic cell death. This process reprograms the suppressive tumor microenvironment, characterized by increased DC maturation, elevated CD8⁺ T-cell infiltration, and a reduction in regulatory T cells. These findings support enhanced cuproptosis-driven metalloimmunotherapy as a strategy for treating TNBC. Briefly, in neoadjuvant settings, preoperative EsCu@NPs reduce tumor burden, decrease minimal residual disease, curb postsurgical recurrence and spontaneous lung metastasis, translating into prolonged survival. Notably, combination with anti-PD-1 checkpoint blockade yields synergy, significantly enhancing the ICB responsiveness of TNBC and producing improved therapeutic efficacy. Overall, this study demonstrates that EsCu@NPs enable coordinated cuproptosis and immune reprogramming, expanding ICB efficacy and supporting a translatable neoadjuvant strategy in TNBC.</p> Graphical Abstract <p></p>

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Glutathione-depleting self-immolative nanoparticles boost cuproptosis-driven metalloimmunotherapy for triple-negative breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月7日

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  • Yunhai Fu,
  • Xiaoyu Wang,
  • Yinqi Li,
  • Xiaodong Yang,
  • Ziying Yao,
  • Jingwen Wang,
  • Yaxin Zhang,
  • Tianping Li,
  • Yunke Zhu,
  • Zhiyao He

摘要

Despite advances in immunotherapy, triple-negative breast cancer (TNBC) remains a major therapeutic challenge owing to its marked aggressiveness, low immunogenicity, and limited responsiveness to immune checkpoint blockade (ICB). Herein, the esterase-responsive polymeric nanoparticles (EsCu@NPs) are developed. The polymer backbone covalently integrates an L-buthionine sulfoximine prodrug to inhibit glutathione biosynthesis, and the nanoparticle matrix encapsulates an elesclomol-copper complex to promote intratumoral copper accumulation. By concurrently depleting glutathione and perturbing copper homeostasis, EsCu@NPs elicit reinforced cuproptosis stress that is converted into immunogenic cell death. This process reprograms the suppressive tumor microenvironment, characterized by increased DC maturation, elevated CD8⁺ T-cell infiltration, and a reduction in regulatory T cells. These findings support enhanced cuproptosis-driven metalloimmunotherapy as a strategy for treating TNBC. Briefly, in neoadjuvant settings, preoperative EsCu@NPs reduce tumor burden, decrease minimal residual disease, curb postsurgical recurrence and spontaneous lung metastasis, translating into prolonged survival. Notably, combination with anti-PD-1 checkpoint blockade yields synergy, significantly enhancing the ICB responsiveness of TNBC and producing improved therapeutic efficacy. Overall, this study demonstrates that EsCu@NPs enable coordinated cuproptosis and immune reprogramming, expanding ICB efficacy and supporting a translatable neoadjuvant strategy in TNBC.

Graphical Abstract