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

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.