近年来，活性氧（ROS）介导的新兴疗法在癌症治疗中表现出独特的优势。而ROS参与的肿瘤治疗的疗效却受到复杂的肿瘤微环境（TME）的极大限制。在此，提出了一种具有 TME 响应和调节能力的双金属 CaO2@CDs-Fe (CCF) 纳米球，通过具有多米诺效应的多重级联协同治疗策略来提高 ROS 杀伤力。为了应对弱酸性 TME，CCF 会分解，同时细胞内 Ca2+ 上调，并产生大量的 H2O2 和 O2，以逆转抗治疗性 TME。然后，暴露的CF核心可以充当芬顿剂和声敏剂，在受调节的TME中产生过量的ROS，从而增强协同CDT/SDT。与钙超载相结合，活性氧诱导的氧化应激增强将导致更严重的线粒体损伤和细胞凋亡。此外，CCF还可以降低GPX4的表达并扩大脂质过氧化作用，同时引起铁死亡和细胞凋亡。这些损伤信号最终将启动损伤相关分子模式，激活免疫反应，实现优异的抗肿瘤效果。这种出色的多米诺 ROS/钙负载协同效应赋予 CCF 优异的抗癌效果，可在体外和体内通过细胞凋亡/铁死亡/ICD 有效消除肿瘤。© 2024 Wiley‐VCH GmbH。

Reactive oxygen species (ROS)-mediated emerging treatments exhibit unique advantages in cancer therapy in recent years. While the efficacy of ROS-involved tumor therapy is greatly restricted by complex tumor microenvironment (TME). Herein, a dual-metal CaO2@CDs-Fe (CCF) nanosphere, with TME response and regulation capabilities, are proposed to improve ROS lethal power by a multiple cascade synergistic therapeutic strategy with domino effect. In response to weak acidic TME, CCF will decompose, accompanied with intracellular Ca2+ upregulated and abundant H2O2 and O2 produced to reverse antitherapeutic TME. Then the exposed CF cores can act as both Fenton agent and sonosensitizer to generate excessive ROS in the regulated TME for enhanced synergistic CDT/SDT. In combination with calcium overloading, the augmented ROS induced oxidative stress will cause more severe mitochondrial damage and cellular apoptosis. Furthermore, CCF can also reduce GPX4 expression and enlarge the lipid peroxidation, causing ferroptosis and apoptosis in parallel. These signals of damage will finally initiate damage-associated molecular patterns to activate immune response and to realize excellent antitumor effect. This outstanding domino ROS/calcium loading synergistic effect endows CCF with excellent anticancer effect to efficiently eliminate tumor by apoptosis/ferroptosis/ICD both in vitro and in vivo.© 2024 Wiley‐VCH GmbH.