由于肺转移中铜积累不足、铜外流机制和高度免疫抑制的肿瘤微环境（TME），铜凋亡的疗效受到限制。在此，构建了一种可吸入纳米装置（CLDCu），成功克服了铜凋亡的缺点。 CLDCu 由 Cu2-壳聚糖壳和负载双硫仑 (DSF) 的低分子量肝素-生育酚琥珀酸酯 (LMWH-TOS, LT) 核组成。制备的CLDCu可被吸入并在肺部病灶处大量积聚（63.6%），比静脉注射高56.5倍。在肿瘤细胞内，温和的酸性触发 DSF 和 Cu2+ 的共同释放，从而生成双（二乙基二硫代氨基甲酸酯）-铜（CuET）来阻止 Cu 流出蛋白 ATP7B 并形成有毒的 Cu2+，导致铜凋亡增强。同时，释放的壳聚糖与 CLDCu 诱导的铜凋亡配合，激活干扰素基因刺激剂 (STING) 途径，显着增强树突状细胞 (DC) 的成熟，并唤起先天性和适应性免疫。在肺转移小鼠模型中，发现 CLDCu 可以通过吸入诱导铜凋亡并逆转免疫抑制性 TME。此外，CLDCu 与抗程序性细胞死亡蛋白配体-1 抗体 (aPD-L1) 结合可激发更强的抗肿瘤免疫力。因此，将铜凋亡与 STING 激活相结合的纳米医学是肿瘤免疫治疗的一种新策略。© 2024 作者。

Due to the insufficient Cu+ accumulation, Cu+ efflux mechanism, and highly immunosuppressive tumor microenvironment (TME) in lung metastasis, the cuproptosis efficacy is limited. Herein, an inhalable nanodevice (CLDCu) is constructed to successfully overcome the drawbacks of cuproptosis. CLDCu consists of a Cu2+-chitosan shell and low molecular weight heparin-tocopherol succinate (LMWH-TOS, LT) core with disulfiram (DSF) loading. The prepared CLDCu can be inhaled and accumulate in large amounts in lung lesions (63.6%) with 56.5 times higher than intravenous injection. Within tumor cells, the mild acidity triggers the co-release of DSF and Cu2+, thus generating bis(diethyldithiocarbamate)-copper (CuET) to block Cu+ efflux protein ATP7B and forming toxic Cu+, leading to enhanced cuproptosis. Meanwhile, the released chitosan cooperates with CLDCu-induced cuproptosis to activate stimulator of interferon genes (STING) pathway, which significantly potentiates dendritic cells (DCs) maturation, as wells as evokes innate and adaptive immunity. In lung metastatic mice model, CLDCu is found to induce cuproptosis and reverse the immunosuppressive TME by inhalation administration. Moreover, CLDCu combined with anti-programmed cell death protein ligand-1 antibody (aPD-L1) provokes stronger antitumor immunity. Therefore, nanomedicine that combines cuproptosis with STING activation is a novel strategy for tumor immunotherapy.© 2024 The Authors.