PANoptosis has recently emerged as a potential approach to improve the immune microenvironment. However, current methods for inducing PANoptosis are limited. Herein, through biological screening, the rational use of the nutrient metal ions Cu 2+ and Zn 2+ had great potential to induce PANoptosis. Inspired by these findings, we successfully developed hydrazided hyaluronic acid–modified zinc copper oxide (HZCO) nanoparticles as a PANoptosis inducer to potentiate immunotherapy. Bioactive HZCO actively delivered Cu 2+ and Zn 2+ while disrupting the cellular intrinsic ion metabolism pathway, resulting in double-stranded DNA release and organelle damage in cancer cells. Simultaneously, this process triggered the formation of PANoptosome and the activation of PANoptosis. HZCO-induced PANoptosis inhibited tumor growth and activated potent antitumor immune response, thereby enhancing the effectiveness of anti–programmed cell death 1 therapy. Overall, our work provides an insight into the development of PANoptosis inducers and the design of synergistic immunotherapy strategies.

中文翻译：

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双金属过氧化物纳米颗粒通过破坏离子稳态诱导 PANoptosis 以增强免疫治疗


PANoptosis 最近已成为改善免疫微环境的一种潜在方法。然而，目前诱导 PANoptosis 的方法有限。在此，通过生物筛选，合理利用营养金属离子 Cu 2+ 和 Zn 2+ 具有诱导 PANoptosis的巨大潜力。受这些发现的启发，我们成功开发了酰肼透明质酸修饰的氧化锌铜 （HZCO） 纳米颗粒作为增强免疫治疗的 PANoptosis 诱导剂。生物活性 HZCO 主动递送 Cu 2+ 和 Zn 2+，同时破坏细胞内源性离子代谢途径，导致癌细胞双链 DNA 释放和细胞器损伤。同时，这个过程触发了 PANoptosome 的形成和 PANoptosis 的激活。HZCO 诱导的 PANoptosis 抑制肿瘤生长并激活有效的抗肿瘤免疫反应，从而增强抗程序性细胞死亡 1 疗法的有效性。总体而言，我们的工作为 PANoptosis 诱导剂的开发和协同免疫治疗策略的设计提供了见解。