Zinc-copper bimetallic nanoplatforms trigger photothermal-amplified cuproptosis and cGAS-STING activation for enhancing triple-negative breast cancer immunotherapy

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Triple-negative breast cancer (TNBC) is characterized by high rates of metastasis and recurrence, along with a low sensitivity to immunotherapy, resulting in a paucity of effective therapeutic strategies. Herein, we have developed polydopamine-coated zinc-copper bimetallic nanoplatforms (Cu-ZnO2@PDA nanoplatforms, abbreviated CZP NPs) that can efficiently induce photothermal amplified cuproptosis and cGAS-STING signaling pathway activation, thereby reversing the immunosuppressive tumor microenvironment of TNBC, upregulating PD-L1 expression, and boosting the efficacy of anti-programmed death-ligand 1 antibody (αPD-L1)-based immunotherapy. Within the acidic tumor microenvironment (TME), CZP NPs spontaneously release copper and zinc ions and hydrogen peroxide, generating highly oxidative hydroxyl radicals and downregulating iron-sulfur cluster proteins. These actions lead to the disruption of mitochondrial integrity, the release of mitochondrial DNA (mtDNA) and irreversible cuproptosis. The further synergy between mtDNA and zinc ions potentiates the activation of the cGAS-STING signaling pathway, triggering a robust antitumor immune response and sensitizing TNBC to αPD-L1 therapy. Additionally, using an 808 nm near-infrared laser for photothermal therapy significantly augments these effects, resulting in a cascade amplification of therapeutic efficacy against TNBC. The strategic combination of CZP NPs with αPD-L1 markedly bolsters antitumor immunity and suppresses tumor growth. Collectively, our findings present a promising synergistic strategy for TNBC treatment by linking cuproptosis, cGAS-STING activation, photothermal therapy, and immunotherapy.

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