：基于芬顿或芬顿样反应的化学动力疗法（CDT）已成为一种有前景的癌症治疗方法。然而，癌细胞自噬介导的自我保护机制对CDT的疗效提出了重大挑战。在此，我们开发了金属-DNA 纳米复合物 (DAC-Mn)，通过 DNAzyme 抑制自噬来增强 CDT。具体来说，DACs-Mn中的锰基催化剂用于产生高羟基自由基（•OH），杀死癌细胞，而DACs-Mn中掺入的ATG5 DNAzyme则抑制自噬相关蛋白的表达，从而提高CDT的功效。通过破坏细胞在严重氧化应激下的自我保护途径，这种新的 DACs-Mn 方法被发现可以在体外和体内模型中协同增强 CDT，有效放大肿瘤特异性氧化损伤。值得注意的是，金属-DNA纳米复合物还可以诱导免疫原性细胞死亡（ICD），从而抑制肿瘤转移。具体而言，在小鼠双侧肿瘤模型中，CDT 和自噬抑制联合免疫检查点阻断疗法显示出作为原发性和转移性肿瘤新型有效治疗方式的巨大潜力。© 2023 Wiley-VCH GmbH。

: Chemo-dynamic therapy (CDT) based on the Fenton or Fenton-like reaction has emerged as a promising approach for cancer treatment. However, autophagy-mediated self-protection mechanisms of cancer cells pose a significant challenge to the efficacy of CDT. Herein, we developed metal-DNA nanocomplexes (DACs-Mn) to enhance CDT via DNAzyme inhibition of autophagy. Specifically, Mn-based catalyst in DACs-Mn was used to generate highly hydroxyl radicals (•OH) that kill cancer cells, while the ATG5 DNAzyme incorporated into DACs-Mn inhibited the expression of autophagy-associated proteins, thereby improving the efficacy of CDT. By disrupting the self-protective pathway of cells under severe oxidative stress, this novel approach of DACs-Mn was found to synergistically enhance CDT in both in vitro and in vivo models, effectively amplifying tumor-specific oxidative damage. Notably, the Metal-DNA nanocomplexes can also induce immunogenic cell death (ICD), thereby inhibiting tumor metastasis. Specifically, in a bilateral tumor model in mice, the combined approach of CDT and autophagy inhibition followed by immune checkpoint blockade therapy shown significant potential as a novel and effective treatment modality for primary and metastatic tumors.© 2023 Wiley-VCH GmbH.