Cancer remains a leading cause of mortality worldwide, with breast cancer incidence among women showing a steady increase in recent years [1], [2]. Despite significant advancements in early detection and treatment, breast cancer continues to account for a substantial proportion of cancer-related deaths in women, emphasizing the urgent need for more effective and targeted therapeutic approaches. Breast cancer is broadly classified into three major subtypes: hormone receptor-positive/ERBB2-negative, ERBB2-positive, and triple-negative [3], [4], [5]. Treatment strategies are tailored based on the cancer subtype, disease stage, and individual patient characteristics. For instance, radiotherapy is frequently employed as an adjuvant therapy following surgery to eliminate residual tumor cells and prevent recurrence in cases of non-metastatic breast cancer [6], [7]. In recent decades, increasing attention has been directed toward nanomedicine as a promising field for achieving enhanced therapeutic efficacy and improving patient outcomes.

In recent years, therapeutic strategies targeting ion metabolism have attracted significant attention due to their ability to disrupt intracellular ion and redox homeostasis, both of which are crucial for tumor survival [8], [9], [10], [11]. Metal ions such as iron, copper, and calcium play pivotal roles in maintaining this balance [12], [13]. Dysregulation of ion homeostasis has emerged as a promising mechanism for inducing cell death in cancer therapy. Calcium, for instance, is essential for mitochondrial function and is tightly regulated at a stable concentration of approximately 10−7 mol/L. Calcium-based nanoparticles, such as CaCO3 and CaO2, have been widely employed in cancer treatment to induce calcium dysregulation [14], [15], [16]. When these nanoparticles disrupt intracellular calcium levels, they cause calcium overloading, leading to severe cellular stress and triggering cell death. Similarly, ferroptosis, a non-apoptotic form of cell death, is characterized by membrane lipid peroxidation mediated by redox-active metal ions [17], [18], [19]. For example, Qin and colleagues developed a metal-organic framework (MOF) nanocatalyst to disrupt iron homeostasis, effectively inducing ferroptosis for tumor therapy [20]. Copper, another critical trace element, plays an integral role in sustaining intracellular redox balance. Disruption of copper metabolism can trigger a programmed cell death mechanism known as cuproptosis [21], [22], [23], [24]. This process is characterized by the aggregation of lipoylated proteins and the loss of Fe-S clusters, resulting in severe cytotoxic stress. Numerous nanoplatforms have been designed to regulate copper ion levels, thereby inducing cuproptosis and inhibiting tumor cell proliferation. These approaches demonstrate significant potential for advancing cancer treatment through targeted ion metabolism disruption.

Radiotherapy is now widely applied for clinical oncology treatment. Ionizing radiation induces multiple forms of cell death, including apoptosis, necrosis, autophagy, and ferroptosis [25]. Among these, it frequently triggers immunogenic cell death (ICD), which stimulates systemic immune responses against tumors. However, the immunosuppressive tumor microenvironment (TME), characterized by elevated levels of glutathione (GSH) and hydrogen peroxide (H2O2), poses significant barriers to the effectiveness of radiotherapy and immunotherapy [26], [27], [28]. Recent findings indicate that ferredoxin 1 (FDX1) and lipoyl synthase (LIAS) proteins are upregulated in residual tumor tissues following radiotherapy [29]. This upregulation may enhance tumor cell sensitivity to copper ion-mediated cuproptosis. Further, dihydrolipoamide S-acetyltransferase (DLAT), which is increased during cuproptosis, contributes to inflammation within tumor tissues. This inflammation enhances tumor immunogenicity and supports the activation of immunotherapy [30], [31]. Copper ions (Cu²⁺) present a promising approach to overcoming the challenges of immunosuppressive TME. Cu²⁺ depletes intracellular GSH, thereby inhibiting tumor cells' self-repair mechanisms. Moreover, reduced Cu⁺ catalyzes the conversion of H2O2 into cytotoxic reactive oxygen species (ROS), intensifying oxidative stress, inducing cell death, and amplifying the ICD effect [32]. However, endogenous H2O2 levels in tumor cells are typically insufficient to sustain these reactions at a level necessary for significant cell death [33]. This limitation highlights the potential of designing a nanoplatform capable of initiating a cascade reaction to induce cuproptosis, enhance radiosensitization, and activate immune responses through ICD. Such a strategy holds promise for overcoming the immunosuppressive TME and improving cancer treatment outcomes.

Inspired by the challenges posed by the immunosuppressive tumor microenvironment (TME) and the limitations of radiotherapy, a core-shell nanoparticle (NP), ZnO2@Cu, was designed to enhance therapeutic outcomes. This nanoparticle leverages a novel combination of features to modulate the TME, overcome radioresistance, and promote immunogenic cell death (ICD), thereby enhancing immune responses. ZnO2@Cu incorporates a ZnO2 core and a copper-ion-doped polydopamine shell, enabling it to synergize with radiotherapy and induce cascade reactions. First H2O2 was slowly generated from core ZnO2 in acidic microenvironment, which provided abundant H2O2 source. Next, since polydopamine can be dissolved in existence of overexpressed intratumoral H2O2, copper-based shell reacted with H2O2 to induce cascade reactions resulting in cuproptosis. By addressing the key limitations of conventional therapies, ZnO2@Cu demonstrates potential for effective tumor elimination while activating systemic immune responses. This study highlights the development, characterization, and therapeutic evaluation of ZnO2@Cu in both in vitro and in vivo settings, providing a promising approach for the integration of nanomedicine and immunotherapy. Thus ZnO2@Cu was found to modulate the radioresistant TME by H2O2 and GSH consumption, mediate cuproptosis, and synergize with radiotherapy. This approach effectively eliminated tumors while promoting immune responses through the ICD effect, as demonstrated in both in vitro and in vivo studies(Scheme 1).