Nanomedicine leverages cuproptosis-mediated cGAS-STING activation to enhance antitumor immunity

Abstract

The cGAS-STING pathway is a cornerstone of innate immunity, sensing cytosolic DNA to initiate potent type I interferon and inflammatory responses. Its targeted activation represents a promising strategy to overcome cancer immunosuppression and resistance. However, the clinical translation of conventional STING agonists is hindered by poor pharmacokinetics, lack of tumor specificity, and systemic toxicity. Recent advances highlight a crucial interaction between the cGAS-STING pathway and cuproptosis, a novel copper-dependent form of regulated cell death driven by mitochondrial metabolism. Nanomedicine offers a transformative platform for exploiting this synergy. Specifically, engineered nanoplatforms can induce cuproptosis within tumor cells, leading to mitochondrial damage and the release of mitochondrial DNA (mtDNA) into the cytosol. This released mtDNA serves as a potent endogenous ligand to activate the cGAS-STING pathway. The subsequent cascade results in robust production of type I interferons and pro-inflammatory cytokines, which remodel the tumor microenvironment by promoting dendritic cell maturation, macrophage repolarization, and cytotoxic T-cell infiltration. This bridges a unique immunogenic cell death mechanism with the activation of systemic antitumor immunity. This review outlines the cGAS-STING signaling axis and its role in cancer, details the functional interplay with cuproptosis, and focuses on recent nanomedicine strategies designed to leverage this cuproptosis–mtDNA –cGAS-STING axis to potentiate antitumor immunity. We further discuss current challenges and future perspectives for this innovative combinatorial immunotherapy approach. Overall, this article highlights promising nanomedicine-based avenues that leverage the cGAS-STING–cuproptosis interplay for cancer therapy.

Graphical Abstract

Introduction

The immune system plays a critical role in surveilling and eliminating malignant cells, a process fundamental for antitumor immunity. Harnessing this intrinsic defense mechanism, cancer immunotherapy—particularly immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 and CTLA-4 axes—has revolutionized oncology by reactivating dysfunctional T cells and achieving durable responses in various cancers [1]. However, the clinical benefits of ICB are limited by low response rates in many solid tumors, primary and acquired resistance mechanisms, and immune-related adverse events [2]. These limitations underscore the urgent need for novel strategies that can more effectively initiate and amplify the cancer-immunity cycle, particularly by robustly activating innate immune sensing to stimulate a potent and sustained adaptive antitumor response.

The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS-STING) pathway serves as a central cytosolic DNA sensor, linking cellular stress and damage to the induction of type I interferons and pro-inflammatory cytokines, thereby orchestrating innate and adaptive immunity [3].In the context of cancer, activation of the cGAS-STING pathway can promote dendritic cell maturation, enhance tumor antigen presentation, stimulate cytotoxic T lymphocyte infiltration, and reverse immunosuppressive microenvironments, positioning it as a powerful therapeutic target for immunotherapy [4, 5]. Despite this promise, the clinical translation of conventional cGAS-STING agonists is hampered by poor pharmacokinetics, rapid systemic clearance, lack of tumor specificity, and dose-limiting toxicities [6].

Nanomedicine offers a transformative platform to overcome these delivery challenges. By encapsulating or conjugating therapeutic agents, nanoparticles can enhance tumor accumulation via the enhanced permeability and retention (EPR) effect, enable active targeting and provide controlled release, thereby improving the efficacy and safety of STING pathway agonists [7–12]. Recently, an intriguing interplay has been discovered between the cGAS-STING pathway and a novel regulated cell death modality known as cuproptosis—a copper-dependent form of cell death driven by mitochondrial metabolism and characterized by the aggregation of lipoylated proteins [13]. Inducing cuproptosis functions as a novel therapeutic targets for overcoming cancer drug resistance [14].Targeting cuproptosis with nanomaterials can improve cancer immunotherapy [15, 16].Emerging evidence suggests that inducing cuproptosis can trigger mitochondrial damage and the release of mitochondrial DNA (mtDNA), which in turn serves as a potent endogenous ligand to activate the cGAS-STING pathway [17].

This convergence presents a unique opportunity for leveraging nanomedicine to simultaneously induce cuproptosis and activate cGAS-STING signaling within tumors. Such a strategy could initiate a self-amplifying cycle of immunogenic cell death and innate immune activation, leading to robust and systemic antitumor immunity. This review will explore this synergistic paradigm, focusing on how nanomedicine can be engineered to exploit the cuproptosis–cGAS-STING axis, thereby overcoming current limitations in cancer immunotherapy and opening new avenues for combination treatment strategies.

cGAS-STING signaling pathway

Overview of the cGAS-STING signaling pathway

The cGAS-STING signaling axis consists of cyclic GMP-AMP synthase (cGAS) and the stimulator of interferon genes (STING) (Fig. 1). Functioning upstream of STING [18, 19], cGAS acts as a cytosolic DNA sensor that recognizes pathogenic or misplaced double-stranded DNA in a sequence-independent manner, thereby initiating a type I interferon (IFN)-dependent innate immune response essential for host defense against infections [3].In addition to microbial DNA, cGAS can be activated by endogenous DNA—such as mitochondrial DNA or nuclear chromatin released upon genomic stress—linking this pathway to autoinflammatory diseases, sterile inflammation, and cellular senescence [3]. Upon binding dsDNA, cGAS undergoes a conformational shift that enhances its catalytic activity [20–24], leading to the synthesis of 2′,3′-cyclic GMP-AMP (cGAMP) from ATP and GTP [25]. This secondary messenger binds to and activates STING, a ∼40 kDa transmembrane adaptor protein residing in the endoplasmic reticulum (ER) [19, 25, 26], prompting its oligomerization into dimers and higher-order complexes [27, 28]. Activated STING then translocates to the ER–Golgi intermediate compartment, where it recruits TBK1 and IKK kinases. TBK1 mediates phosphorylation of itself and STING, resulting in IRF3 phosphorylation and activation, while IKK promotes NF-κB signaling via IκBα phosphorylation [3]. These events facilitate nuclear translocation of IRF3 and NF-κB, driving the expression of type I interferons (e.g., IFN-β) and proinflammatory cytokines such as TNF and IL-6 [29]. Together, these responses coordinate antimicrobial and antiviral defense mechanisms [3]. Following activation, STING is targeted for degradation through endolysosomal pathways [3].Beyond its classical role in infection, the cGAS-STING pathway also senses tissue damage and cellular stress, and participates in regulating autophagy, metabolism, senescence, and programmed cell death. It is crucial for maintaining tissue homeostasis, and its dysregulation has been associated with a spectrum of disorders, including inflammatory, autoimmune, degenerative, and malignant diseases [3].

Fig. 1.

The cGAS-STING Signaling Cascade. The cGAS-STING pathway is initiated by the accumulation of cytosol double-stranded DNA(dsDNA), which are introduced by virus, bacteria, dead cells, mitochondria and cancer cells, et al. cGAS recognizes dsDNA exposed during pathogen infection or cellular stress, leading to produce the second messenger, 2′3′ cyclic GMP-AMP (cGAMP). Upon accumulation, cGAMP binds to STING located on the endoplasmic reticulum (ER) membrane and facilitates further pathway activation. The binding of cGAMP to STING mediates STING dimerization and translocation from the ER to the Golgi apparatus, where STING forms a complex with TANK-binding kinase 1 (TBK1), which, through auto-phosphorylation and STING phosphorylation, mediates recruitment

The role of cGAS-STING in cancer

Epigenetic silencing of the cGAS-STING pathway represents a common immune evasion mechanism in cancer, and its downregulation has been observed across numerous human malignancies [30, 31].This suppression occurs through diverse processes —including epigenetic alterations, post-translational modifications (PTMs), and dysregulated intracellular metabolic pathways—collectively contributing to therapy resistance. Key regulatory factors include DNA and histone modifiers, non-coding RNAs (ncRNAs), and RNA modification writers such as those mediating 5-methylcytosine (m⁵C). These aberrant epigenetic changes promote oncogenesis by disrupting normal gene expression, altering protein dynamics, and facilitating malignant transformation [32]. Specifically, DNA methylation [33], histone methylation and demethylation [34–39], m⁵C modification [40], and ncRNA-mediated regulation [41, 42] have been implicated in the suppression of cGAS and STING. Additionally, PTMs—including ubiquitination [43–46], phosphorylation [47–49], methylation [50, 51], palmitoylation [52], and lactylation [53]—modulate the expression and function of cGAS and STING through multiple mechanisms. Metabolic pathways such as glucose [40], fatty acid [54], serine [55], purine synthesis [56], and ATP metabolism [57] further regulate this axis. A deeper understanding of these metabolic reprogramming mechanisms may reveal therapeutic vulnerabilities to reactivate cGAS-STING signaling and enhance antitumor immunity.

In oncology, cGAS-STING activation exerts antitumor effects by stimulating innate immunity, promoting senescence in pre-malignant cells, enhancing conventional therapy responses, and inducing regulated cell death (RCD) via both interferon (IFN)-dependent and -independent mechanisms [4, 5, 58]. These functions underscore its role as a tumor-suppressive pathway with therapeutic promise. However, monotherapy with STING agonists has shown limited clinical efficacy in patients with advanced cancer. Recent preclinical studies using in vitro and in vivo models have begun to uncover how cancer cells autonomously and non-autonomously evade cGAS-STING-mediated immune surveillance [33, 34, 36, 40, 41].

Cuproptosis in cancers

Core mechanism of Cuproptosis

Cuproptosis was first introduced as a distinct form of regulated cell death by Tsvetkov et al. in 2022 [13]. The foundation for this concept stems from earlier observations that copper can induce cytotoxicity and exhibit anticancer activity. Studies had shown that disulfiram (DSF) possesses anticancer properties [59], that copper itself triggers cell death [60], accelerates cancer cell death [61], and can induce a non-apoptotic form of programmed cell death [59]. Further work revealed that the copper ionophore elesclomol induces apoptosis and selectively transports copper to mitochondria to kill cancer cells [62], while also enhancing the antitumor efficacy of disulfiram [59]. Critical regulators of copper toxicity were identified, including ferredoxin 1 (FDX1) and lipoyl synthase (LIAS) [63], laying the groundwork for the formal conceptualization of cuproptosis.

As an essential micronutrient, copper serves as a structural or catalytic cofactor for numerous enzymes and is involved in key biological processes such as mitochondrial oxidative phosphorylation (OXPHOS), iron homeostasis, connective tissue cross-linking, ROS detoxification, and signal transduction [64, 65]. However, copper can also be cytotoxic. Overload leads to harmful reactive oxygen species (ROS) via Fenton reactions and disrupts iron-sulfur clusters. Chronic copper exposure is linked to various diseases, including cancer, and it is recognized as a crucial factor in tumor growth and metastasis [66]. Despite this, the precise mechanisms of copper-induced toxicity and cell death remained unclear, and known cellular targets failed to fully explain cellular responses to copper stress.

The term “cuproptosis” emerged from efforts to decipher copper-induced toxicity [63]. In 2019, Tsvetkov et al. described copper-dependent cell death while investigating the anticancer mechanism of elesclomol (ES) [63]. They found that ES increases cancer cell sensitivity to proteasome inhibitors in a multiple myeloma model. Mechanistically, ES-bound Cu²⁺ interacts with mitochondrial FDX1 and is reduced to Cu⁺, elevating ROS levels [63, 67]. Although initially attributed to lipid peroxidation [68], subsequent research in 2022 redefined this process as cuproptosis—a unique form of cell death marked by aggregation of lipoylated mitochondrial enzymes and loss of Fe–S cluster proteins [13]. Tsvetkov et al. demonstrated that excess intracellular Cu²⁺ is shuttled to mitochondria by ionophores. There, FDX1 reduces Cu²⁺ to Cu⁺, which binds directly to lipoylated components of the dihydrolipoamide S-acetyltransferase (DLAT) complex, triggering protein aggregation, Fe–S cluster destabilization, proteotoxic stress, and ultimately cell death (Fig. 2) [13]. Notably, this form of cell death could not be suppressed by inhibitors of apoptosis, ferroptosis, or necroptosis. Antioxidants such as N-acetylcysteine, α-tocopherol, ebselen, and JP4-039 also failed to rescue cells, indicating that ROS—including mitochondrial ROS—are not central to cuproptosis. However, glutathione (GSH) mitigated ES–Cu toxicity by chelating intracellular copper, underscoring the distinct nature of cuproptosis compared to other cell death pathways [13].

Fig. 2.

Core Mechanisms of cuproptosis

Crucially, cuproptosis is tightly linked to mitochondrial metabolism. Cancer cells reliant on mitochondrial respiration were far more sensitive to ES–Cu than those dependent on glycolysis. Inhibitors of the electron transport chain (e.g., rotenone, antimycin A) or mitochondrial pyruvate uptake (e.g., UK5099) prevented cuproptosis. Hypoxia (1% O₂), which shifts cells toward glycolysis, also reduced sensitivity. This metabolic dependency distinguishes cuproptosis from ferroptosis, which requires glucose uptake and pyruvate oxidation. Together, these findings establish cuproptosis as a novel form of copper-dependent, oxidative stress-independent cell death driven by mitochondrial metabolism.

Leveraging Cuproptosis to exert anti-cancer

Leveraging cuproptosis to exert anti-cancer effects involves several distinct mechanisms. Each mechanism capitalizes on the unique pathway of copper-induced cell death, which centers on mitochondrial metabolism, protein lipoylation, and proteotoxic stress. Below are the key strategies, each explained in a separate paragraph with specific examples and supporting references from the text.

Inducing Cuproptosis via copper ionophores

Copper ionophores are compounds that facilitate the transport of copper into cells, leading to intracellular copper overload and triggering cuproptosis. These molecules selectively deliver copper to mitochondria, where it binds to lipoylated proteins such as DLAT (dihydrolipoamide S-acetyltransferase), causing aggregation, proteotoxic stress, and cell death. Elesclomol forms a complex with extracellular Cu²⁺ and transports it into mitochondria. There, Cu²⁺ is reduced to Cu⁺ by FDX1, leading to DLAT aggregation and cuproptosis. Elesclomol–Cu has shown efficacy in prostate cancer by enhancing docetaxel sensitivity via the DLAT/mTOR pathway [69]. Disulfiram, an FDA -approved anti-alcoholism drug, acts as a copper ionophore and forms CuET (bis-diethyldithiocarbamate–copper), which induces cuproptosis in pituitary tumors and other cancers [70].

Sensitizing tumors to Cuproptosis via metabolic reprogramming

Cuproptosis is highly dependent on mitochondrial metabolism. Tumor cells with high oxidative phosphorylation (OXPHOS) activity are more susceptible to copper-induced death. Conversely, glycolytic tumors are less sensitive. Targeting metabolic pathways can thus sensitize tumors to cuproptosis.4-Octyl itaconate (4-OI) inhibits glycolysis by targeting GAPDH, shifting CRC cells toward mitochondrial metabolism and enhancing elesclomol–Cu-induced cuproptosis [71]. Inhibition of the electron transport chain (ETC) or pyruvate uptake reduces cuproptosis, confirming its reliance on mitochondrial respiration [13].

Overcoming drug resistance via Cuproptosis induction

Cuproptosis can reverse resistance to chemotherapy, targeted therapy, and immunotherapy by inducing an alternative cell death pathway [14]. Elesclomol–Cu overcomes docetaxel resistance in prostate cancer by inducing DLAT/mTOR-dependent cuproptosis [69]. Disulfiram–Cu reverses resistance to BRAF inhibitors in thyroid cancer by relieving feedback activation of MAPK/ERK and PI3K/AKT pathways [72]. Cuproptosis can reverse resistance to conventional therapies, such as proteasome inhibitors (PIs) and platinum-based drugs [73]. ES has been shown to sensitize PI-resistant melanoma and lung cancer cells by targeting mitochondrial metabolism [74]. Similarly, DSF/Cu complex reduces cancer stem cell populations and reverses cisplatin resistance in cervical and bladder cancers [75]. Nanoparticles like CuET NPs have demonstrated efficacy in cisplatin-resistant lung cancer models by inducing cuproptosis and inhibiting tumor growth.

Enhancing immunotherapy via cuproptosis-mediated immune activation

Cuproptosis can remodel the tumor microenvironment (TME) and activate anti-tumor immunity, particularly when combined with immune checkpoint inhibitors. Elesclomol–Cu induces immunogenic cell death (ICD) and activates the cGAS -STING pathway in dendritic cells, promoting T-cell infiltration and enhancing anti-PD-1/PD-L1 efficacy [76].In clear cell renal cell carcinoma, cuproptosis activates the cGAS-STING pathway, leading to dendritic cell maturation and cytokine production, which enhances anti-tumor immunity [76]. Cuproptosis can enhance the efficacy of immune checkpoint blockade (ICB) by increasing tumor immunogenicity. For example, copper ionophores like ES upregulate PD-L1 expression in cancer cells, and when combined with anti-PD-1/PD-L1 antibodies, they promote T-cell-mediated tumor killing [77].

Small-molecule inducers of Cuproptosis

Several small molecules can induce or sensitize to cuproptosis without exogenous copper, reducing metal-related side effects.

Zinc pyrithione (ZnPT) disrupts copper homeostasis and promotes DLAT oligomerization in triple-negative breast cancer [78].Sorafenib and erastin, known ferroptosis inducers, also enhance cuproptosis in liver cancer by depleting GSH and increasing lipoylated protein aggregation [79].

Synergistic induction of Cuproptosis and other cell death pathways

Cuproptosis can be combined with ferroptosis, apoptosis, or autophagy to create synergistic anti-cancer effects, especially in resistant tumors [80].There is significant crosstalk between cuproptosis and ferroptosis, another form of regulated cell death. Copper ionophores like ES and DSF can concurrently induce both pathways. For example, in colorectal cancer, ES increases mitochondrial copper and reactive oxygen species (ROS), leading to degradation of SLC7A11 and glutathione depletion, which promotes ferroptosis [68]. Similarly, sorafenib and erastin—known ferroptosis inducers—enhance cuproptosis by stabilizing FDX1 and promoting lipoylated protein aggregation [79]. DSF/Cu complex was shown to induce both cuproptosis and ferroptosis, accompanied by glutathione depletion and lipid peroxidation, enhancing cell death in hepatocellular carcinoma [81].This dual induction strategy has shown enhanced anti-tumor efficacy in hepatocellular carcinoma models.

Nanomedicine leverages Cuproptosis to exert anti-cancer effects

The nanoparticle-mediated cuproptosis represents a promising strategy for enhancing cancer therapy, particularly when combined with other treatment modalities. Nanoparticles are engineered to accumulate copper within tumor cells, where excessive copper ions bind to lipoylated proteins in the tricarboxylic acid (TCA) cycle, leading to proteotoxic stress, mitochondrial dysfunction, and reactive oxygen species (ROS) generation. This process not only directly kills tumor cells but also promotes the release of damage-associated molecular patterns (DAMPs), such as HMGB1 and ATP, which activate dendritic cells (DCs) and stimulate the cGAS-STING pathway, resulting in robust T-cell infiltration and antitumor immune responses [82–84]. Nanomedicines leverage cuproptosis to achieve targeted antitumor effects by specifically increasing intracellular copper levels in cancer cells while minimizing off-target toxicity [83].This is primarily accomplished through the design of copper -based nanomaterials that can deliver Cu ions or copper ionophores directly to tumor sites, where they induce mitochondrial proteotoxic stress via the aggregation of lipoylated proteins—such as dihydrolipoamide S-acetyltransferase (DLAT)—and disruption of Fe-S cluster proteins, leading to cell death [83].Copper-based nanomedicines leverage the novel mechanism of cuproptosis to exert antitumor effects by selectively increasing intracellular copper ion levels in cancer cells, leading to mitochondrial dysfunction and proteotoxic stress. These nanomaterials enhance copper delivery through targeted approaches, improved cellular uptake, and controlled release, thereby overcoming limitations such as nonspecific distribution and short half-life associated with conventional copper ionophores [85]. Nanoparticles serve as ideal platforms to induce cuproptosis due to their ability to preferentially accumulate in tumor tissues via the enhanced permeability and retention (EPR) effect, be modified for active targeting, and respond to the specific tumor microenvironment (TME) [82]. They overcome key challenges in cuproptosis induction, such as high intracellular GSH levels, hypoxia, and the lack of tumor specificity of free copper ionophores [82].The copper-based nanomaterials exploit the mechanism of cuproptosis to achieve antitumor effects [86]. These nanomaterials enhance copper accumulation within cancer cells, leading to mitochondrial dysfunction, aggregation of lipoylated proteins such as DLAT, and disruption of Fe–S cluster protein synthesis, ultimately triggering cuproptosis. Below is a point-by-point analysis of how cuproptosis can be utilized to kill tumor cells and overcome treatment resistance, with specific examples and references from the text [87].

Induction of tumor cell cuproptosis via nanoplatforms. Cuproptosis is a copper-dependent form of regulated cell death driven by mitochondrial metabolism. Nanoparticles can deliver copper ions directly to tumor cells, where they bind to lipoylated enzymes in the TCA cycle, leading to protein aggregation, loss of Fe–S cluster proteins, and cell death.Tang et al. developed a platelet membrane-coated Cu₂O/TBP-2 system (PTC) that releases Cu²⁺ under light irradiation. This system induced DLAT aggregation and Fe–S cluster loss, leading to cuproptosis in 4T1 breast cancer cells and inhibition of lung metastasis [88]. Copper-based nanomaterials can precisely deliver Cu ions to tumor sites, inducing cuproptosis while minimizing systemic toxicity. For instance, MOF-199, a Cu-based metal–organic framework with high Cu content (~ 30%), degrades in the acidic tumor microenvironment (TME), releasing Cu²⁺ ions that trigger cuproptosis and immunogenic cell death in glioblastoma models. This system demonstrated enhanced antitumor efficacy via intranasal administration, bypassing the blood–brain barrier [89].

Reversal of chemotherapy resistance. Cuproptosis bypasses apoptotic resistance mechanisms by targeting mitochondrial metabolism. Copper-based nanomaterials can also deplete GSH, a key molecule in chemoresistance, thereby sensitizing tumor cells to chemotherapy. Li et al. designed a ZnPc-TK-DOX prodrug assembly (CCNAs) that releases doxorubicin (DOX) upon light irradiation. Cu²⁺ ions enhanced DOX efficacy via Fenton-like reactions and cuproptosis, overcoming hypoxia-induced chemoresistance in PC-3 prostate cancer cells [90].Cuproptosis inducers can overcome resistance to conventional chemotherapeutics like cisplatin. CuET (a complex of diethyldithiocarbamate and Cu) was shown to induce cuproptosis in cisplatin-resistant A549 lung cancer cells. By bypassing glutathione (GSH) -mediated detoxification pathways, CuET resists drug efflux and restores sensitivity to platinum-based drugs [75].

Enhancement of immunotherapy. Cuproptosis can trigger immunogenic cell death (ICD), which promotes antitumor immunity by releasing damage-associated molecular patterns (DAMPs) such as calreticulin (CRT) and HMGB1. Zhao et al. developed Cu-THBQ/AX nano-MOFs that induced cuproptosis and released XMD8-92 to inhibit macrophage efferocytosis. This shifted immunosuppressive apoptosis to pro-inflammatory secondary necrosis, enhancing antitumor immunity [91].Cuproptosis can remodel the immunosuppressive TME and enhance immune checkpoint blockade. NP@ESCu, a ROS-sensitive nanoplatform co-delivering elesclomol (ES) and Cu, not only induced cuproptosis but also increased T-cell infiltration and PD-L1 expression. When combined with anti-PD-L1 antibodies, it converted “cold” tumors into “hot” ones, improving systemic antitumor immunity [92].

Overcoming targeted therapy resistance. By disrupting mitochondrial function and redox balance, cuproptosis can target cancer cells resistant to kinase inhibitors or other targeted agents.The GOx@[Cu(tz)] system utilized glucose oxidase to starve tumor cells and enhance cuproptosis. This approach sensitized tumors to metabolic stress, overcoming adaptive resistance mechanisms [93].While not explicitly detailed in the text, cuproptosis mechanisms—such as DLAT aggregation and Fe–S cluster disruption—can interfere with oncogenic signaling pathways, potentially overcoming resistance to targeted drugs. Further studies are needed to explore this application fully.

Synergy with photodynamic therapy (PDT). Cuproptosis and PDT synergize through shared oxidative stress mechanisms. Copper nanoparticles can generate ROS via Fenton-like reactions, while PDT consumes GSH and produces ROS, collectively enhancing tumor cell killing [94]. Xie et al. constructed Cu-doped hollow Prussian blue NPs (CHPB) loaded with ICG and O₂. Under laser irradiation, they produced ROS and induced cuproptosis, significantly improving PDT outcomes [95]. Cuproptosis can be enhanced by PDT through ROS amplification [83]. CJS-Cu nanoparticles acted as a type-I photosensitizer, generating O₂•⁻ under light irradiation, which reduced Cu²⁺ to Cu⁺, promoting cuproptosis. The ROS storm further depleted GSH and damaged Fe–S cluster proteins, augmenting therapeutic efficacy [96].

Combination with photothermal therapy (PTT).Copper-based nanomaterials can serve as both PTT agents and cuproptosis inducers. The heat generated by PTT can trigger copper ion release, enhancing cuproptosis [94]. CHPB NPs exhibited photothermal conversion under 808 nm laser, which promoted O₂ release and enhanced PDT, while Cu ions induced cuproptosis [97].Cu-based nanomaterials with strong NIR absorption can combine PTT and cuproptosis [83]. DMMA@Cu₂₋ₓSe nanoparticles released Cu ions under acidic TME and laser irradiation, leading to mitochondrial dysfunction and Cu aggregation. The photothermal effect accelerated Cu release and enhanced cuproptosis, achieving synergistic tumor ablation [98].

Integration with sonodynamic therapy (SDT). Although not explicitly detailed in the text, the principle of using copper nanomaterials to enhance SDT can be inferred: Cu ions could amplify ROS generation under ultrasound, synergizing with cuproptosis. While not directly cited, similar Cu-based nanosystems could be designed to respond to ultrasound, leveraging Cuproptosis and ROS for SDT [99]. Ultrasound-responsive Cu-based systems enable deep-tumor cuproptosis. SonoCu, a macrophage-membrane-camouflaged Cu@ZIF-8 nanoplatform, generated ROS under ultrasound and induced DLAT oligomerization. This combination of SDT and cuproptosis effectively treated hypoxic tumors [100].

Augmentation of radiotherapy (RT). Copper ions can enhance radiation-induced ROS production and disrupt DNA repair mechanisms. Cuproptosis may also be induced in radioresistant cells through mitochondrial targeting. Though not explicitly covered, the review implies that Cu-based NPs could be used to sensitize tumors to RT by increasing oxidative stress and cuproptosis [101]. Cuproptosis sensitizes tumors to radiation by degrading Fe–S clusters and enhancing ROS production [83]. PWCu, a Cu-containing polyoxometalate, released Cu⁺ under X-ray irradiation, inducing cuproptosis and activating systemic immune responses. This approach overcame radiation resistance in multiple tumor models [102].

In summary, nanoparticle-mediated cuproptosis offers a multi-faceted approach to combat cancer by directly killing tumor cells, reversing various forms of therapy resistance, and synergizing with established treatments such as PDT, PTT, SDT, and RT. The rational design of copper-based nanoplatforms holds great potential for future translational cancer therapy.

Nanomedicine induce Cuproptosis to activate cGAS-STING in cancers

Cuproptosis represents a promising therapeutic strategy against cancer by exploiting mitochondrial metabolism and proteotoxic stress. However, the effective induction of cuproptosis in tumors faces significant challenges, including high intracellular GSH levels, hypoxic microenvironments, and the lack of tumor specificity of free copper ionophores, which can lead to systemic toxicity and suboptimal efficacy. Nanomedicine offers a powerful and versatile platform to overcome these limitations. By engineering nanoplatforms that can target tumors, modulate the local microenvironment, and control the release of copper ions or ionophores, it becomes possible to selectively induce cuproptosis within cancer cells. Critically, this nanomaterial-driven cuproptosis not only directly kills tumor cells but also initiates a potent immunogenic cascade. As introduced earlier, the mitochondrial damage characteristic of cuproptosis results in the release of mitochondrial DNA (mtDNA) into the cytosol. This released mtDNA serves as a key endogenous ligand to activate the cGAS-STING pathway, thereby bridging a unique form of regulated cell death with the activation of innate and adaptive antitumor immunity. This section delves into the strategic application of nanomedicine to leverage the synergistic interaction between cuproptosis and the cGAS-STING pathway. We elucidate the core mechanistic link that unifies this approach, discuss the key design principles of nanoplatforms engineered to exploit it, and detail the resulting immunological consequences that potentiate antitumor immunity.

The mechanistic axis: Cuproptosis as an upstream trigger for cGAS-STING activation

A compelling and unified mechanistic model, consistently demonstrated across a diverse array of nanomedicines, positions the induction of cuproptosis as a potent upstream trigger for the activation of the cGAS-STING pathway. This axis effectively bridges a unique form of metal-induced cell death with robust antitumor immunity. The core sequence of events is as follows: Nanomaterial-driven cuproptosis—characterized by mitochondrial metabolic disruption, proteotoxic stress, and the aggregation of lipoylated proteins such as dihydrolipoamide S-acetyltransferase (DLAT)—causes direct damage to mitochondrial integrity [13]. This damage invariably results in the release of mitochondrial DNA (mtDNA) into the cytosol [17, 103–105]. The liberated mtDNA is identified as the critical endogenous ligand that initiates the cGAS-STING signaling cascade [106]. Upon sensing cytosolic mtDNA, cGAS synthesizes the second messenger 2’,3’-cGAMP, which activates STING, leading to the phosphorylation of TBK1 and IRF3 [3].The subsequent nuclear translocation of IRF3 drives the production of type I interferons (e.g., IFN-β) and pro-inflammatory cytokines. This cascade, initiated by cuproptotic stress, is the fundamental link that transforms a cell death event into an immunogenic signal.

Engineering nanoplatforms to Harness the axis: key design principles and strategies

Nanomedicine offers a transformative platform to co-opt this mechanistic axis by overcoming the limitations of conventional small-molecule inducers (e.g., poor pharmacokinetics, lack of tumor specificity) [7–12]. The rational design of nanoplatforms focuses on several key principles to efficiently induce cuproptosis and ensure subsequent cGAS-STING activation:

Controlled Release of Metal Ions: A primary strategy involves the design of nanomaterials that release copper ions (Cu²⁺/Cu⁺) within the tumor. These can be copper-based nanoparticles (e.g., Cu₂O, Cu₃P) [88, 107], copper-containing metal-organic frameworks (MOFs) [89, 103], or nanocomposites that deliver copper ionophores like elesclomol (ES) or disulfiram (DSF) [77, 108].The release is often engineered to be responsive to the tumor microenvironment (TME), such as low pH or high glutathione (GSH) levels, ensuring spatial specificity [109, 110].

Synergistic Delivery of STING Agonists or Cofactors: Many advanced platforms co-deliver components that directly potentiate the cGAS-STING pathway alongside copper, creating a synergistic activation. A common approach is the incorporation of manganese (Mn²⁺), which acts both as a cGAS cofactor enhancing its sensitivity to DNA and as a STING agonist [103, 109, 111]. Other designs include the delivery of classic STING agonists or the use of biomaterials like chitosan, which itself can enhance STING signaling in dendritic cells [108].

Mitochondrial Targeting and Damage Amplification: To maximize cuproptotic efficacy, nanoplatforms are often functionalized to target mitochondria specifically. This is achieved using mitochondrial-targeting ligands (e.g., triphenylphosphonium) or molecules like glycyrrhetinic acid that promote mitochondrial uptake [106, 112]. Furthermore, strategies to amplify mitochondrial stress—such as combining cuproptosis inducers with photodynamic therapy (PDT) agents, mitophagy inhibitors, or metabolic modulators—are employed to ensure sufficient mtDNA release [104, 105].

Combination with Other Therapeutic Modalities: The cuproptosis-cGAS-STING axis is frequently integrated with established therapies to achieve multimodal synergy. Nanoplatforms are designed to concurrently enable photothermal therapy (PTT), sonodynamic therapy (SDT), radiotherapy (RT), or chemotherapy. These combinations can enhance copper ion release, increase overall oxidative stress, and cause additional DNA damage, all of which feed into and amplify the immunogenic signaling cascade [94, 97, 101, 113].

These design principles are exemplified by the wide range of nanoplatforms summarized in Table 1, each engineered to navigate biological barriers and selectively ignite this immunogenic axis within tumors.

Table 1.

Summary of Nanomedicine-Induced Cuproptosis leading to cGAS-STING activation in cancer therapy

Nanoplatform	Key Components	Nanoparticle Type	Mechanism of Cuproptosis Induction	Mechanism of cGAS-STING Activation	Tumor Model	Ref
CGNPs	Self-accelerating copper -based nanoplatform	Inorganic nanoparticle (Copper-based)	Mitochondrial damage, proteotoxic stress, mtDNA release	Cytosolic mtDNA activates cGAS-STING	Triple-negative breast cancer	[17]
CMG	Cu²⁺ and Mn²⁺ releasing MOF	MOF	Cu²⁺ release induces cuproptosis, mtDNA release	Mn²⁺ acts as cGAS agonist; mtDNA synergizes cGAS-STING	Cancer immunotherapy (general)	[103]
Cu-MOF@CDDP	Cu²⁺ and cisplatin-loaded MOF	MOF	Cu²⁺ induces cuproptosis, cisplatin causes DNA damage	Nuclear and mtDNA fragments activate cGAS-STING	Colorectal cancer	[113]
CMCNs@HA	Cu-Mn composite nanoparticles	Composite nanoparticle (Cu-Mn)	Cu²⁺ induces cuproptosis, depletes GSH, alleviates hypoxia	Mn²⁺ activates cGAS-STING; mtDNA synergizes	Tumor microenvironment remodeling	[109]
TCe6@Cu/TP5 NPs	Cu²⁺ and photosensitizer-loaded brain-targeting assembly	Coordination polymer / Brain-targeting assembly	Cu²⁺ and PDT induce mitochondrial damage and mtDNA release	Cytosolic mtDNA activates cGAS-STING	Glioblastoma	[104]
PCM nanoinducer	Cu⁺-loaded metal-phenolic coordination nanoparticles	Coordination polymer nanoparticle (Metal-phenolic)	Cu⁺ aggregates DLAT, inhibits respiration, releases mtDNA	mtDNA activates cGAS-STING; mitophagy inhibition enhances signal	Ultrasound-enhanced therapy	[105]
OPMNs-ZCS@siPD-L1	Zn-doped CuS nanoflowers with siPD-L1 in microneedles	Inorganic nanoparticle (Copper sulfide) / Microneedle system	Cu²⁺ triggers cuproptosis, Zn²⁺ enhances cGAS activity	mtDNA release and Zn²⁺ synergize to activate cGAS-STING	Melanoma	[115]
CG/MC/U-M	CuGA network and carbonyl manganese biomimetic platform	Biomimetic platform / Coordination network	Cu⁺ induces cuproptosis and mitochondrial damage	Mn²⁺ promotes STING activation; mtDNA enhances cGAS sensing	Metastatic adrenal cortical carcinoma	[111]
CMF IMP	Cu0.5Mn2.5O4 NPs and monomethyl fumarate implant	Inorganic nanoparticle implant	CMO NPs induce cuproptosis and mtDNA release	Mn²⁺ and mtDNA synergistically activate cGAS-STING	Breast cancer	[114]
CLDCu	Inhalable Cu²⁺-chitosan/DSF core-shell nanoparticles	Core-shell nanoparticle (Polymer-based)	CuET formation inhibits ATP7B, induces cuproptosis	Chitosan enhances STING activation in dendritic cells	Lung metastasis	[108]
cLipG/CuET	Mitochondria-targeting liposome with GA and CuET	Liposome (Mitochondria-targeting)	GA opens MPTP, Cu(II) enters mitochondria to induce cuproptosis	mtDNA release activates cGAS-STING in macrophages	Cholangiocarcinoma	[112]
ZCPO@HA	Zn²⁺ and Cu²⁺-based inhalable nanoparticles	Inorganic nanoparticle (Zinc/Copper-based)	Cu⁺-mediated DLAT aggregation and Fe-S cluster disruption	Zn²⁺ induces mtDNA release and cGAS activation	Colorectal cancer	[116]
Cu-DPPZ-Py⁺	Mitochondria-targeted copper complex	Metal complex (Mitochondria-targeted)	Cuproptosis triggers mitochondrial dysfunction and mtDNA release	mtDNA activates cGAS-STING pathway	General cancer immunity	[106]
CZP NPs	Polydopamine-coated Zn-Cu bimetallic nanoparticles	Bimetallic nanoparticle (Polydopamine-coated)	Cu²⁺ induces cuproptosis via DLAT aggregation and Fe-S depletion	Zn²⁺ enhances cGAS phase separation; mtDNA activates STING	Triple-negative breast cancer	[110]
Cu₃P nanocubes	Biodegradable copper phosphide nanocubes	Inorganic nanocube (Copper phosphide)	Cu ions induce cuproptosis and mitochondrial stress	DAMPs and mtDNA activate cGAS-STING; PD-L1 upregulation	Sono-immunotherapy	[107]
CD/Cu₃P	Carbon dot/Cu₃P heterojunction nanoplatform	Heterojunction nanoplatform (Carbon dot/Cu₃P)	Cu⁺ release induces cuproptosis, enhanced ROS from SDT/CDT	mtDNA release activates cGAS-STING	Enhanced sono-immunotherapy	[117]

Downstream immunological consequences: remodeling the tumor microenvironment and potentiating antitumor immunity

The activation of the cGAS-STING pathway via cuproptosis-induced mtDNA release orchestrates a profound remodeling of the tumor immune microenvironment, transitioning it from an immunosuppressive (“cold”) state to an immunologically active (“hot”) one. The downstream consequences form a coordinated immune response loop.

Innate Immune Activation and Antigen-Presenting Cell Maturation: The type I interferons and cytokines produced upon STING activation act as potent signals for innate immune cells. A critical outcome is the maturation of dendritic cells (DCs), which enhances their ability to capture tumor antigens released from cuproptotic cells and present them to T cells [109, 17, 105]. Concurrently, tumor-associated macrophages are often repolarized from a pro-tumorigenic (M2) to an anti-tumorigenic (M1) phenotype [112].

Activation and Infiltration of Cytotoxic T Lymphocytes: The matured DCs migrate to tumor-draining lymph nodes to prime naïve T cells. The cytokine milieu (e.g., CXCL10) further promotes the infiltration of activated CD8⁺ cytotoxic T lymphocytes (CTLs) into the tumor core [105, 114]. This step is crucial for executing direct tumor cell killing.Synergy with Immune Checkpoint Blockade (ICB): Notably, the cuproptosis-cGAS-STING axis often leads to the upregulation of immune checkpoint molecules like PD-L1 on tumor cells, an adaptive resistance mechanism [107]. While this could suppress T-cell function, it concurrently creates a rationale for combination therapy with αPD-1/αPD-L1 antibodies. This combination effectively “blocks the brakes” on the newly activated T cells, leading to significantly enhanced therapeutic efficacy in preclinical models and converting immunologically unresponsive tumors into responsive ones [110].

In summary, the immunological consequence of harnessing this axis is the establishment of a self-amplifying cycle: cuproptosis provides the immunogenic fuel (antigens and mtDNA), cGAS-STING activation provides the inflammatory spark, and the resulting immune response reshapes the TME to support sustained antitumor activity, which can be further unleashed by combination immunotherapies.

Summary of representative nanoplatforms

The diverse nanomedicine strategies that implement the cuproptosis-cGAS-STING axis are summarized in Table 1 below, highlighting their key components, mechanisms, and tumor model applications. This table provides a consolidated overview of the exemplars discussed within the mechanistic and design framework above.Subsequent sections elucidate how nano-platforms are designed to activate these two potent immunogenic mechanisms —either sequentially or concurrently—thereby remodeling the tumor microenvironment and potentiating antitumor immunity(Table 1).

The study demonstrated that the self-accelerating copper-based nanoplatform (CGNPs) induces cuproptosis in triple-negative breast cancer cells by causing mitochondrial damage, proteotoxic stress, and the release of mitochondrial DNA (mtDNA) into the cytosol [17] (Fig. 3). This cytosolic mtDNA serves as the key immunogenic signal, initiating the cGAS-STING pathway. The resulting production of type I interferons and pro-inflammatory cytokines promotes dendritic cell maturation, macrophage repolarization, and T-cell infiltration, thereby activating both innate and adaptive immunity. In this paradigm, the immunogenicity of cuproptosis is fundamentally mediated through the liberated mtDNA and its engagement of the cGAS-STING signaling cascade [17].

Fig. 3.

Schematic illustration of (a) the preparation process of CGNPs nanoplatforms and (b) the “copper-bomb” strategy for potent antitumor therapy and activated immune response via a self-accelerating cycle of starvation therapy and cuproptosis

Zhang et al. developed a self-amplifying nanoplatform (CMG) that synergistically enhances cuproptosis and activates the cGAS-STING pathway for improved cancer immunotherapy. The mechanism involves the nanoplatform’s degradation in the tumor microenvironment, which releases Cu²⁺ to induce cuproptosis, causing mitochondrial damage and the release of mtDNA [103]. Concurrently, the released Mn²⁺ acts as a direct cGAS-STING agonist. The cytosolic mtDNA from cuproptosis and the Mn²⁺ ions function in concert to robustly activate the cGAS-STING pathway, leading to type I interferon production and potent innate and adaptive immune activation. This design illustrates a strategic convergence where cuproptosis-generated mtDNA and a co-released agonist (Mn²⁺) synergize to maximize cGAS-STING stimulation [103] (Fig. 4).

Fig. 4.

Schematic illustration of CMG synthesis and starvation-enhanced cuproptosis combined with synergistic cGAS–STING activation for potentiated cancer immunotherapy

Copper-coordinated nano-framework Cu-MOF@CDDP potently inhibits colorectal cancer stemness and enhances chemo-immunotherapy efficacy by synergistically activating cuproptosis and the cGAS-STING pathway [113]. The nanoparticles release Cu²⁺ and cisplatin intracellularly, where Cu²⁺ induces cuproptosis—disrupting mitochondrial metabolism and generating reactive oxygen species—leading to nuclear and mitochondrial DNA damage. These DNA fragments, originating from both genomic and mitochondrial sources, converge to activate the cGAS-STING pathway.These DNA fragments then activate the cGAS-STING pathway, promoting dendritic cell maturation and T-cell infiltration, which amplifies anti-tumor immunity. Overall, the therapy leverages cuproptosis to contribute a crucial source of mtDNA that complements chemotherapy-induced DNA damage, creating a powerful combined trigger for cGAS -STING-dependent immunity [113] (Fig. 5).

Fig. 5.

Copper-Based Metal-Organic Frameworks Repurposed to Target Cancer Stemness and Enhance Sensitivity to Chemo-immunotherapy.copper-ion delivery via Cu-MOF@CDDP nanoparticles induces cuproptosis and potentiates chemo-immunotherapy in colorectal cancer. Upon cellular internalization, the nanoparticles release cisplatin (CDDP) and Cu²⁺ in the high-glutathione tumor microenvironment. CDDP generates nuclear DNA damage, while Cu²⁺ triggers cuproptosis by disrupting mitochondrial metabolism, leading to mitochondrial DNA release. The cytosolic accumulation of DNA fragments from both sources activates the cGAS-STING pathway, initiating a type I interferon response and dendritic cell maturation. Concurrently, Cu²⁺ depletes glutathione and downregulates stemness-related proteins (e.g., ZEB1, c-MYC), suppressing cancer stemness. Together, cuproptosis-driven cGAS-STING activation and stemness inhibition synergize with cisplatin-induced DNA damage to enhance antitumor immunity and sensitize tumors to chemo-immunotherapy

Cu-Mn nanocomposite CMCNs@HA significantly enhances tumor cuproptosis by remodeling the tumor microenvironment through GSH depletion and hypoxia alleviation, while concurrently activating the cGAS-STING pathway via released Mn²⁺ ions to initiate potent antitumor immunity [109]. The nanoplatform releases Cu²⁺ to induce cuproptosis, which disrupts mitochondrial metabolism and promotes immunogenic cell death, thereby generating cytosolic DNA fragments that synergize with Mn²⁺ to robustly activate the cGAS-STING pathway, leading to dendritic cell maturation, cytotoxic T-cell infiltration, and inhibition of both primary and metastatic tumors. In summary, cuproptosis serves as an upstream trigger that promotes immunogenic stress and DNA release, which in turn activates the cGAS-STING pathway downstream to orchestrate a comprehensive antitumor immune response [109](Fig. 6).

Fig. 6.

Schematic diagram showing that CMCNs@HA augments cuproptosis and CDT, leading to enhanced tumor cell killing via TME remodeling. Upon accumulation in the tumor, the GSH- and pH-responsive Cu–Mn composite nanoplatform (CMCNs@HA) releases Cu²⁺ from CuO₂ and Mn²⁺ from MnO₂ in the acidic, high-GSH tumor microenvironment. Released Cu²⁺ induces cuproptosis by disrupting mitochondrial metabolism and aggregating lipoylated proteins, while Mn²⁺ acts as a Fenton-like catalyst to generate hydroxyl radicals, augmenting oxidative stress and cuproptosis. Concurrently, Mn²⁺ ions activate the cGAS-STING pathway, triggering type I interferon production and dendritic cell maturation, which promotes cytotoxic T-cell infiltration and a systemic anti-tumor immune response. Moreover, the O₂ generated via MnO₂-catalyzed decomposition of H₂O₂ alleviates tumor hypoxia, further sensitizing cells to cuproptosis. The released Mn²⁺ also serves as an activatable T₁ MRI contrast agent, enabling real-time imaging of tumor targeting and treatment progression. Together, cuproptosis-driven immunogenic cell death and cGAS-STING activation synergize to suppress primary tumor growth and inhibit distant metastasis

Chen et al. developed a brain-targeting copper-coordination nanoassembly (TCe6@Cu/TP5 NPs) that effectively crosses the blood-brain barrier and induces mitochondrial impairment in glioblastoma through combined photodynamic therapy and Cu²⁺-triggered cuproptosis [104]. The resulting mitochondrial damage, characterized by reactive oxygen species accumulation and proteotoxic stress, leads to the release of mitochondrial DNA into the cytosol. This cytosolic mtDNA then serves as a potent ligand to activate the cGAS-STING pathway, initiating a robust innate immune response characterized by type I interferon production, which subsequently promotes dendritic cell maturation and cytotoxic T-cell infiltration, thereby reprogramming the immunosuppressive tumor microenvironment. In summary, cuproptosis acts upstream of the cGAS-STING pathway by generating the critical ligand—mtDNA—required for its activation [104] (Fig. 7).

Fig. 7.

The therapeutic potential of TCe6@Cu/TP5 against glioblastoma (GBM).The nanoassembly triggers cuproptosis via mitochondrial Cu accumulation, inducing ATP depletion and ROS generation. Mitochondrial damage releases DNA fragments that activate the cGAS-STING pathway, promoting innate immunity. Concurrent AMPK activation degrades PD-L1, synergizing with TP5-enhanced T cell responses for potent anti-GBM immunotherapy

Yu et al. demonstrated that the PCM nanoinducer, through metal-phenolic coordination, delivers Cu⁺ to induce cuproptosis by aggregating lipoylated DLAT and inhibiting mitochondrial respiration, thereby generating profound proteotoxic stress within mitochondria [105]. This stress is amplified by ultrasound-activated Ce6 and, crucially, the co-delivered mitophagy inhibitor Mdivi-1 prevents the clearance of damaged mitochondria, leading to the substantial cytosolic release of mtDNA. The liberated mtDNA then acts as a potent endogenous ligand to activate the cGAS-STING pathway, resulting in the production of type I interferons and CXCL10, which subsequently stimulate robust innate and adaptive anti-tumor immunity, including NK cell activation and cytotoxic T-cell infiltration. In summary, cuproptosis acts upstream to instigate mitochondrial damage and mtDNA release, which serves as the critical trigger for the downstream activation of the cGAS-STING signaling axis [105](Fig. 8).

Fig. 8.

Schematic diagram depicting the fabrication of PCM nanoinducers and their role in activating the proteotoxic mtDNA–cGAS–STING signaling cascade to enable robust anti-tumor immunotherapy.The PCM nanoinducer delivers Cu⁺ to mitochondria, inducing DLAT aggregation and cuproptosis. This proteotoxic stress disrupts mitochondrial integrity, promoting mtDNA release into the cytosol. Released mtDNA activates the cGAS-STING pathway, which is further amplified by the co-delivered mitophagy inhibitor preventing mtDNA clearance. The resulting IFN-β production enhances DC maturation, NK cell activation, and T cell-mediated antitumor immunity

Tao et al. developed oxygen pump microneedles (OPMNs-ZCS@siPD-L1) loaded with zinc-doped copper sulfide nanoflowers and siPD-L1, which significantly enhanced melanoma immunotherapy by synergistically inducing cuproptosis and activating the cGAS-STING pathway [115]. The nanoflowers release Cu²⁺ in the acidic tumor microenvironment, triggering cuproptosis that disrupts mitochondrial integrity and leads to mtDNA release into the cytoplasm; concurrently, Zn²⁺ ions enhance cGAS enzyme activity. The cytosolic mtDNA is recognized by cGAS, initiating the STING signaling cascade that promotes interferon production and robust innate immune activation. Thus, cuproptosis serves as an upstream inducer of mtDNA release, which downstream activates the cGAS-STING pathway to amplify antitumor immunity [115](Fig. 9).

Fig. 9.

Schematic illustration of the preparation and anti-tumor mechanism of ZCS@siPD-L1. ZCS NFs are synthesized using quaternary chitosan (QCS, 10% w/w) and PVP (90% w/w) as stabilizers, followed by the electrostatic loading of siPD-L1 to form ZCS@siPD-L1. Upon administration, oxygen pump microneedles (OPMNs) enhance drug penetration and alleviate hypoxia through the dissolution of SPC to generate oxygen bubbles. The system further potentiates anti-tumor immunity via a dual strategy: cuproptosis-mediated activation of the STING pathway and induction of immunogenic cell death (ICD) act as a “throttle-increasing” mechanism to boost immunogenicity, while siPD-L1-mediated reversal of immunosuppression and OPMNs-driven hypoxia relief collectively function as a “brake-releasing” approach to remodel the tumor microenvironment (TME)

Li et al. demonstrated that the biomimetic nanoplatform CG/MC/U-M, by co-delivering a copper-gallic acid network (CuGA) and carbonyl manganese, simultaneously induces cuproptosis and activates the cGAS-STING pathway to potentiate anti-tumor immunity [111]. Specifically, the released Cu⁺ from CuGA triggers cuproptosis by aggregating lipoylated DLAT and disrupting mitochondrial metabolism, leading to mitochondrial damage and the release of mtDNA. Concurrently, the decomposition of Mn₂(CO)₁₀ releases Mn²⁺ ions, which directly promote STING activation. The cytosolic mtDNA, liberated as a result of cuproptosis-induced mitochondrial disruption, acts as a potent agonist for the cGAS sensor, thereby synergizing with Mn²⁺ to robustly activate the cGAS-STING pathway and stimulate a type I interferon response, dendritic cell maturation, and cytotoxic T-cell infiltration. In summary, cuproptosis acts upstream to instigate mitochondrial damage and mtDNA release, which serves as the critical trigger for the downstream activation of the cGAS-STING signaling axis [111](Fig. 10).

Fig. 10.

Schematic overview of the preparation method and working mechanism of CG/MC/U-M for metastatic adrenal cortical carcinoma (ACC).The CG/MC/U-M nanoassembly releases Cu²⁺ to induce cuproptosis and mitochondrial damage, leading to mtDNA release into the cytosol. Concurrently, released Mn²⁺ acts as a cGAS cofactor, enhancing cGAS-STING pathway activation. This promotes type I interferon production and dendritic cell maturation, synergistically reshaping the immunosuppressive tumor microenvironment and boosting antitumor immunity

Jiang et al. developed a puncture-delivered gelatin methacryloyl xerogel implant (CMF IMP) co-loaded with Cu0.5 Mn2.5 O4 nanoparticles (CMO NPs) and monomethyl fumarate (MMF) for enhanced breast cancer immunotherapy [114].The CMO NPs induced cuproptosis in tumor cells, causing mitochondrial damage and the release of mtDNA into the cytosol, while MMF further amplified mtDNA release through mitochondrial stress [114].The liberated mtDNA, in synergy with Mn²⁺ ions released from the nanoparticles, potently activated the cGAS-STING pathway, triggering a robust innate immune response characterized by type I interferon production [114].This cGAS-STING activation, combined with immunogenic cell death (ICD) induced by CMO NPs, promoted dendritic cell maturation, enhanced CD8 + T cell infiltration, and synergized with αPD-1 therapy to remodel the tumor microenvironment and inhibit both primary and metastatic tumors. In summary, cuproptosis acts upstream by inducing mitochondrial damage and mtDNA release, which downstream activates the cGAS-STING pathway to initiate and amplify antitumor immunity [114](Fig. 11).

Fig. 11.

Schematic Representation of Implant Preparation and Deployment Leading to Intratumoral Release of CMO NPs and MMF, Which Promotes mtDNA Release and Alters the Tumor Microenvironment.The implant releases CMO NPs to induce cuproptosis, causing mitochondrial damage and mtDNA release into the cytosol. The liberated mtDNA synergizes with Mn²⁺ to activate the cGAS-STING pathway, triggering innate immunity and synergizing with immunogenic cell death to enhance antitumor T-cell responses

Yan et al. developed an inhalable nanoparticle (CLDCu) thatsynergistically enhances cuproptosis and activates the cGAS-STINGpathway to potentiate antitumor immunity in lung metastasis. Thenanoparticle, composed of a Cu²⁺-chitosan shell and a disulfiram(DSF)-loaded core, efficiently accumulates in lung tissues viainhalation [108]. Upon internalization by tumor cells, the acidictumor microenvironment triggers the release of Cu²⁺ and DSF,which react to form CuET and generate Cu⁺ [108]. CuET inhibits theCu⁺ efflux protein ATP7B, leading to intracellular Cu⁺ accumulation,which induces cuproptosis by promoting DLAT aggregation anddestabilizing Fe–S cluster proteins. Concurrently, cuproptosisAccepted manuscriptACCEPTED MANUSCRIPTinitiates immunogenic cell death (ICD), releasing DAMPs such asATP and HMGB1 [108]. The co-released chitosan further amplifiesimmune activation by stimulating the cGAS–STING pathway indendritic cells (DCs), enhancing their maturation and promotingCD8⁺ T cell infiltration. Together, cuproptosis and cGAS-STINGactivation remodel the immunosuppressive tumor microenvironmentand, when combined with αPD-L1, elicit robust systemic antitumorimmunity[108]. In summary, cuproptosis acts upstream to triggerimmunogenic cell death and initiate immune responses, while cGASSTINGactivation serves as a downstream amplifier that enhancesdendritic cell maturation and adaptive antitumorimmunity [108](Fig. 12).

Fig. 12.

Inhalable CLDCu potentiates cuproptosis and activates the cGAS-STING pathway for enhanced immunotherapy against lung metastasis. (A) Synthesis procedure of CLDCu. (B) Schematic representation of CLDCu-mediated amplified cuproptosis and synergistic immunotherapy in vivo

Ge et al. developed a mitochondria-targeting nanoliposome (cLipG/CuET) co-loaded with glycyrrhetinic acid (GA) and copper diethyldithiocarbamate (CuET) for cholangiocarcinoma immunotherapy [112]. The nanoparticle utilizes GA to open mitochondrial permeability transition pores (MPTP), facilitating the entry of Cu(II) into mitochondria where it induces cuproptosis [112]. This copper-dependent mitochondrial damage triggers the release of mtDNA into the cytosol [112]. The cytosolic mtDNA then activates the cGAS-STING pathway in macrophages, leading to the production of type I interferons and pro-inflammatory cytokines. This innate immune activation promotes M1 polarization of tumor -associated macrophages and enhances anti-tumor T cell responses, synergizing with αCTLA-4 checkpoint blockade to transform immunologically “cold” tumors into “hot” ones. In summary, cuproptosis acts upstream by causing mitochondrial damage and mtDNA release, which subsequently initiates the downstream cGAS-STING pathway to potentiate anti-tumor immunity [112](Fig. 13).

Fig. 13.

The clipG/CuET nanocomplex targets tumor cell mitochondria, where GA opens the MPTP to facilitate Cu²⁺ entry. This induces copper-dependent itochondrial dysfunction and cuproptosis, leading to the release of mtDNA into the cytosol. The cytosolic mtDNA activates the cGAS-STING pathway in macrophages, promoting their polarization to the M1 phenotype and enhancing antitumor immunity

Li et al. demonstrated that both inhalable nanoparticle systems, CLDCu and ZCPO@HA, effectively induce cuproptosis in tumor cells—through Cu⁺-mediated DLAT aggregation and Fe-S cluster protein disruption—which acts as an upstream immunogenic trigger by releasing damage-associated molecular patterns (DAMPs) and initiating adaptive immunity [116]. Concurrently, the nanoparticles activate the cGAS-STING pathway: CLDCu does so via chitosan-enhanced STING signaling, while ZCPO@HA leverages Zn²⁺-induced mitochondrial damage and mtDNA release, positioning cGAS-STING as a downstream innate immune amplifier that synergizes with cuproptosis to enhance dendritic cell maturation, T-cell activation, and systemic antitumor immunity [116]. In summary, cuproptosis serves as an upstream immunogenic trigger that initiates cell death and antigen release, while cGAS-STING acts as a downstream innate immune amplifier that enhances and sustains antitumor immune responses [116](Fig. 14).

Fig. 14.

Schematic Illustration of ESCu@HM Mechanism.(A) Preparation of ESCu@HM; (B) ESCu@HM triggers cuproptosis and activates the cGAS–STING pathway for colorectal cancer immunotherapy.The copper-overload-induced cuproptosis causes mitochondrial and nuclear DNA damage, releasing dsDNA fragments. Concurrently, Mn²⁺ released from the degraded MnO₂ shell potently sensitizes cGAS, amplifying the activation of the cGAS-STING pathway. This cascade reprograms the tumor microenvironment by repolarizing macrophages and promoting dendritic cell maturation

Zhu et al. revealed that cuproptosis, induced by mitochondria-targeted copper complexes such as Cu-DPPZ-Py⁺, triggers mitochondrial dysfunction and the release of mtDNA into the cytoplasm, which is sensed by cyclic GMP-AMP synthase (cGAS) to produce cGAMP, thereby activating the STING pathway [106]. This leads to phosphorylation of IRF3, increased IFN-β expression, dendritic cell maturation, and enhanced T-cell immunity, whereas apoptosis via Cu-DPPZ-Ph results in caspase-3 activation and immunosuppression. In essence, cuproptosis acts upstream by promoting mtDNA release to activate the downstream cGAS-STING pathway, bridging metal-induced cell death with antitumor immune responses [106](Fig. 15).

Fig. 15.

Schematic Illustration of Molecular Tools: Structures of Cu-DPPZ-Py + and Cu-DPPZ-Ph, and the Mechanism by Which Cuproptosis Triggers Mitochondrial DNA (mtDNA) Release to Activate Immunity Through the cGAS-STING Pathway. Mitochondria-targeted Cu-DPPZ-Py⁺ induces cuproptosis, leading to mtDNA release into the cytoplasm. This released mtDNA activates the cGAS-STING innate immune pathway, distinct from the immunosuppressive apoptosis triggered by Cu-DPPZ-Ph

Zhou et al. developed a polydopamine-coated zinc-copper bimetallic nanoplatform (CZP NPs) that utilizes photothermal therapy to amplify a synergistic anti-tumor mechanism centered on the relationship between cuproptosis and cGAS-STING activation [110]. The nanoparticles respond to the acidic tumor microenvironment by releasing Cu²⁺ and Zn²⁺ ions, where the Fenton-like reaction generates hydroxyl radicals and induces cuproptosis through DLAT aggregation and depletion of Fe-S cluster proteins, leading to mitochondrial damage and the release of mtDNA [110]. The liberated mtDNA, in conjunction with the Zn²⁺ ions which enhance cGAS phase separation, potently activates the cGAS-STING pathway, resulting in the production of type I interferons and pro-inflammatory cytokines that promote dendritic cell maturation and cytotoxic T-cell infiltration, thereby converting the immunosuppressive tumor microenvironment and sensitizing tumors to αPD-L1 therapy [110]. In summary, cuproptosis acts as the upstream trigger that initiates mitochondrial damage and immunogenic signaling, while cGAS-STING serves as the critical downstream amplifier that potentiates and sustains the innate and adaptive anti-tumor immune response [110](Fig. 16).

Fig. 16.

Schematic illustration of the Cu-ZnO₂@PDA nanoplatform combined with αPD-L1 for enhancing immunotherapy in triple-negative breast cancer.CZP NPs release Cu²⁺ and Zn²⁺ in the acidic TME, inducing cuproptosis and mitochondrial damage. Photothermal therapy amplifies this process, promoting mtDNA release. The cytosolic mtDNA, together with Zn²⁺, activates the cGAS-STING pathway, enhancing DC maturation and T-cell infiltration, and upregulating PD-L1 to sensitize tumors to αPD-L1 therapy

Liu et al. demonstrated that both inhalable nanoparticle systems, CLDCu and ZCPO@HA, effectively induce cuproptosis in tumor cells—through Cu⁺-mediated DLAT aggregation and Fe-S cluster protein disruption—which acts as an upstream immunogenic trigger by releasing damage-associated molecular patterns (DAMPs) and initiating adaptive immunity [118]. Concurrently, the nanoparticles activate the cGAS-STING pathway: CLDCu does so via chitosan-enhanced STING signaling, while ZCPO@HA leverages Zn²⁺-induced mitochondrial damage and mtDNA release, positioning cGAS-STING as a downstream innate immune amplifier that synergizes with cuproptosis to enhance dendritic cell maturation, T-cell activation, and systemic antitumor immunity [118]. In summary, cuproptosis serves as an upstream immunogenic trigger that initiates cell death and antigen release, while cGAS-STING acts as a downstream innate immune amplifier that enhances and sustains antitumor immune responses [118](Fig. 17).

Fig. 17.

Schematic depiction of the preparation (a) and anti-tumor immunotherapy (b) of ZCPO@HA nanoparticles. ZCPO@HA nanoparticles induce cuproptosis, leading to mitochondrial damage and release of mitochondrial DNA (mtDNA). The cytosolic mtDNA activates the cGAS-STING pathway, triggering type I interferon production and enhancing innate antitumor immunity

The study developed biodegradable Cu₃P nanocubes that exhibit tumor-specific degradation, enabling targeted release of copper ions and loaded celastrol within the tumor microenvironment [107]. The released Cu ions induce cuproptosis, which triggers mitochondrial stress and immunogenic cell death (ICD), while simultaneously upregulating PD-L1 expression and activating the cGAS-STING pathway through the release of damage-associated molecular patterns. The activated cGAS-STING signaling enhances dendritic cell maturation and promotes a systemic antitumor immune response, which is further amplified by immune checkpoint blockade. In summary, cuproptosis acts as an upstream immunogenic trigger that activates the downstream cGAS-STING pathway to potentiate antitumor immunity [107](Fig. 18).

Fig. 18.

Schematic illustration of fabricating Cu3P nanocubes via an in-situ phosphating strategy, which enables cuproptosis-enhanced sono-immunotherapy by activating the cGAS-STING pathway and sensitizing tumors to immune checkpoint blockade.Cu₃P sonozymes specifically release Cu ions in tumors to induce cuproptosis, which triggers mitochondrial damage and activates the cGAS-STING pathway, thereby amplifying antitumor immune responses and sensitizing immune checkpoint blockade

The study developed a CD/Cu₃P heterojunction nanoplatform that synergistically combines sonodynamic therapy (SDT), chemodynamic therapy (CDT), and cuproptosis to potentiate antitumor immunity via cGAS-STING activation [117]. The nanoplatform enhances ROS generation through heterojunction engineering and depletes GSH, inducing robust immunogenic cell death (ICD). Critically, the released Cu ions trigger cuproptosis, which disrupts mitochondrial metabolism and releases mitochondrial DNA, thereby activating the cGAS-STING pathway. This cascade promotes dendritic cell maturation, T-cell infiltration, and systemic immune responses, effectively inhibiting both primary and distant tumors. In summary, cuproptosis acts as an upstream trigger that activates the downstream cGAS-STING pathway to amplify antitumor immunity [117](Fig. 19).

Fig. 19.

Schematic diagram illustrating the preparation of CD/Cu3P for augmented sono-immunotherapy via heterojunction enhancement and cuproptosis induction, mediated through activation of the cGAS-STING pathway. The CD/Cu₃P heterojunction platform specifically releases Cu⁺ in tumors, inducing cuproptosis. Enhanced SDT/CDT from the heterojunction amplifies ROS production, collectively causing mitochondrial damage and activating the cGAS-STING pathway, thereby potentiating antitumor immunotherapy

This section presents a compelling and unified mechanistic model, consistently demonstrated across a diverse array of nanomedicines, wherein the induction of cuproptosis acts as a potent upstream trigger for the activation of the cGAS-STING pathway, thereby bridging a unique form of metal-induced cell death with robust antitumor immunity. The central finding is that nanomaterial-driven cuproptosis —characterized by mitochondrial metabolic disruption, proteotoxic stress, and the aggregation of lipoylated proteins—invariably causes mitochondrial damage and the consequent release of mtDNA into the cytosol. This liberated mtDNA is identified as the critical endogenous ligand that initiates the cGAS-STING signaling cascade. The subsequent production of type I interferons and pro-inflammatory cytokines orchestrates a favorable remodeling of the tumor microenvironment, promoting dendritic cell maturation, macrophage repolarization, and cytotoxic T-cell infiltration, which synergistically enhances innate and adaptive immune responses against cancer.

While the central focus of this review is the potent cuproptosis –mtDNA–cGAS-STING axis, it is important to recognize that this paradigm represents one prominent example of a broader conceptual framework: leveraging nanomedicine to couple specific forms of regulated cell death (RCD) with innate immune sensing pathways for enhanced immunotherapy. Other RCD modalities, notably ferroptosis, have also been shown to synergize with cGAS-STING activation, sharing the common endpoint of immunogenic remodeling but often through distinct mechanistic origins [119]. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, can trigger the release of damage-associated molecular patterns (DAMPs) and expose immunogenic signals. This process can remodel the tumor microenvironment and, under certain conditions, lead to the release of nuclear or mitochondrial DNA that may engage cytosolic sensors like cGAS. For instance, a landmark study by De Leon et al. demonstrated that ultrasmall core–shell silica nanoparticles could induce potent antitumor immunity and improve survival by remodeling suppressive melanoma microenvironments [120]. Although the primary cell death mechanism in that study may not have been cuproptosis, the work underscores a critical general principle: engineered nanomaterials can be designed to trigger immunogenic stress and damage-associated molecular patterns release, which in turn can activate innate immune pathways like cGAS-STING. This provides valuable comparative context, showing that the strategic nexus between nanomaterial-induced cell death and immune activation is not limited to a single death mechanism. The conceptual parallel lies in the ability of both cuproptosis-inducing and ferroptosis-inducing (or other RCD-inducing) nanoplatforms to convert immunologically “cold” tumors into “hot” ones by generating endogenous adjuvants (e.g., nucleic acids) and pro-inflammatory cues [120]. This broadened perspective emphasizes that the choice of RCD pathway—be it cuproptosis, ferroptosis, or others—can be tailored based on the tumor’s metabolic vulnerabilities and the desired immune outcome, thereby expanding the arsenal of combinatorial nanomedicine strategies for next-generation cancer immunotherapy [120].

Despite the establishment of this clear cuproptosis-mtDNA-cGAS-STING axis, several critical questions remain unresolved, paving the way for essential future research. A primary unknown is the precise molecular identity and the exact mechanisms governing the translocation of mtDNA from the damaged mitochondria into the cytosol; it is unclear whether this process involves specific pores, mitochondrial permeability transition, or other forms of mitochondrial outer membrane permeabilization. Furthermore, the long-term consequences and potential adaptability of tumors to this therapeutic strategy are not well understood, as cancer cells might develop resistance by downregulating cuproptosis-susceptible proteins, enhancing DNA degradation mechanisms, or evolving ways to suppress STING signaling. The heterogeneity of the tumor microenvironment also presents a significant challenge, as variable factors such as hypoxia, nutrient availability, and the presence of immunosuppressive cells could profoundly influence the efficacy of this nanomedicine approach, potentially leading to inconsistent therapeutic outcomes across different cancer types and individual patients.

Future research directions must therefore focus on elucidating the fundamental cell biology of cuproptosis-induced immunogenicity, particularly the detailed biophysics and biochemistry of mtDNA release. It is also crucial to investigate the potential crosstalk between cuproptosis and other cell death pathways, such as ferroptosis and pyroptosis, to understand if and how they can be co-opted for even more potent immunotherapy. From a translational perspective, future work should prioritize the development of more sophisticated, next-generation nanoplatforms that can dynamically respond to specific tumor microenvironmental cues to precisely control the spatiotemporal release of copper ions and STING agonists, thereby maximizing efficacy while minimizing off-target effects. Comprehensive biodistribution, long-term safety, and potential immunotoxicity profiles of these copper-based nanomaterials require thorough investigation in more advanced, immunocompetent animal models that faithfully recapitulate human cancer immunology. Finally, a key frontier lies in identifying predictive biomarkers that can stratify patients most likely to respond to this therapy, such as the baseline expression of key cuproptosis regulators or components of the STING pathway, to enable personalized and more effective cancer immunotherapy regimens.

Categorization and comparative analysis of nanomedicine platforms for Cuproptosis-Mediated cGAS-STING activation

The diverse nanoplatforms designed to harness the cuproptosis–cGAS-STING axis can be broadly categorized based on their core composition and functional design. The following analysis provides a structured comparison of the major categories, highlighting their mechanisms, advantages, and current limitations.

Copper-Based Metal-Organic frameworks (Cu-MOFs) and inorganic coordination polymers

This category encompasses nanomaterials with structured networks formed by copper ions coordinated with organic linkers (MOFs) or other inorganic components. Examples include Cu-MOF@CDDP [113], CMG (Cu/Mn-based MOF) [103], and enzyme-engineered copper(I) coordination polymers [93].These platforms typically degrade in the tumor microenvironment (TME), releasing Cu²⁺ ions to induce cuproptosis. The concomitant release of other metal ions (e.g., Mn²⁺ from CMG) can directly agonize cGAS or STING. The cuproptosis-induced mtDNA release synergizes with these ions to robustly activate the cGAS-STING pathway [103, 113]. Cu-MOFs and related inorganic coordination polymers offer significant advantages, including high and tunable copper loading capacity, inherent porosity for co-loading therapeutic agents, and degradation responsive to tumor microenvironment cues. However, they face challenges such as potential instability in biological fluids, insufficiently defined long-term biodistribution and biodegradability, and an incomplete understanding of the immunogenicity associated with their organic components or breakdown products.

Metallic and bimetallic nanoparticles (Cu, Cu-Mn, Zn-Cu)

This group includes nanoparticles composed of elemental copper, copper compounds (e.g., Cu₂O, Cu₃P), or bimetallic systems (e.g., Cu-Mn, Zn-Cu). Examples are CGNPs (self-accelerating copper nanoplatform) [17], Cu₃P nanocubes [107], CZP NPs (Zn-Cu bimetallic) [110], and CMCNs@HA (Cu-Mn composite) [109]. These nanoparticles release Cu⁺/Cu²⁺ ions intracellularly or in the TME to trigger cuproptosis. Bimetallic systems often leverage a second metal ion (Mn²⁺, Zn²⁺) to enhance cGAS activity or phase separation, amplifying the sensing of cuproptosis-liberated mtDNA [109, 110, 117].

Metallic and bimetallic nanoparticles offer significant advantages, including relatively simple synthesis, strong catalytic activity for reactive oxygen species (ROS) generation, and photothermal properties that enable combinatory therapies, with bimetallic designs further allowing multimodal immune activation [115]. However, their limitations encompass the risk of uncontrolled ion release causing off-target toxicity, a generally lower drug loading capacity compared to porous materials, and a requirement for careful surface modification to enhance stability and tumor targeting.

Functional hybrid and Core-Shell nanosystems

These are engineered constructs featuring a core (e.g., copper-based material) with a functional shell or hybrid components. Examples include CLDCu (Cu²⁺ -chitosan/DSF core-shell) [108], PCM nanoinducers (metal-phenolic coordination) [105], and CD/Cu₃P heterojunctions [117].The core provides the copper source for cuproptosis, while the shell/hybrid component offers additional functions: controlled release (pH/GSH-responsive), targeting (e.g., brain-targeting ligands), delivery of adjuvants (siRNA, STING agonists), or enhancement of combinatory therapies (SDT, PDT) [104, 105, 108]. Functional hybrid and core-shell nanosystems offer significant advantages, including high design flexibility for multifunctional integration, improved pharmacokinetics and targeting, and the potential for spatiotemporally controlled activation of combined therapies such as cuproptosis and STING signaling. However, these systems also face challenges such as complex and less reproducible fabrication, unpredictable pharmacokinetics and clearance of multi-component structures, and difficulties in scaling up for manufacturing.

Biomimetic and Biomolecule-Based nanoplatforms

Description: This category utilizes natural biomolecules (e.g., chitosan, lipids) or employs biomimetic strategies (e.g., cell membrane coating) to construct nanoparticles. Examples are cLipG/CuET (mitochondria-targeting liposome) [112], CG/MC/U-M (biomimetic vesicles) [111], and platelet membrane-coated systems [88]. These platforms often enhance tumor targeting and cellular uptake. They efficiently deliver copper ionophores (e.g., CuET, ES) or copper complexes to induce cuproptosis. Components like chitosan can themselves stimulate STING pathway in immune cells, creating synergy with cuproptosis-derived signals [108, 111, 112]. Biomimetic and biomolecule-based nanoplatforms offer significant advantages, including enhanced biocompatibility, reduced immunogenicity, and the ability for targeted delivery to specific cells or organelles through biomimetic coatings. However, these systems also face limitations such as constrained drug loading capacity, potential instability, and batch-to-batch variability during production.

Cell-type-specific consequences of STING activation and the guiding role of nanomedicine

The canonical view of the cGAS-STING pathway as a uniformly anti-tumorigenic innate immune sensor requires refinement in light of emerging evidence demonstrating that its functional outcome is critically dependent on the cellular context in which it is activated. STING signaling can elicit divergent, and sometimes opposing, biological effects in different cell types within the TME (TME) and the immune system, presenting both a challenge and an opportunity for therapeutic intervention.

In cancer cells, STING activation has a well-documented dual role. While it can induce senescence, apoptosis, and immunogenic cell death—thereby suppressing tumor growth—persistent or dysregulated STING signaling in malignant cells can also promote pro-tumorigenic outcomes. These include fostering an inflammatory environment conducive to metastasis, enhancing DNA repair mechanisms that confer therapy resistance, and upregulating survival factors such as PD-L1, which facilitates immune evasion [121, 122]. For instance, chronic STING activation in cancer cells has been linked to cancer metastasis [123]. This duality necessitates strategies that can maximize the immunogenic, anti-proliferative effects of STING in cancer cells while minimizing its pro-survival and metastatic functions.

The consequences of STING activation in immune cells are equally complex and cell-type-specific. In dendritic cells (DCs) and macrophages, STING signaling is fundamentally beneficial for antitumor immunity, driving type I interferon (IFN) production, enhancing antigen presentation, and promoting M1-like polarization [3, 29]. However, activation of the STING pathway in lymphocytes can be detrimental. In T cells, particularly CD8⁺ T cells, cell-intrinsic STING signaling has been shown to induce activation-induced cell death (AICD) and functional exhaustion, thereby attenuating the adaptive immune response [124]. STING activation in different cellular compartments can lead to divergent, and sometimes opposing, biological outcomes. For example, STING activation in cancer cells has been reported to exert both pro-tumorigenic and anti-tumorigenic effects, while STING signaling in T and B cells can induce apoptosis [125]. Chromosomal instability (CIN), a hallmark of many cancers characterized by ongoing chromosome mis-segregation and DNA damage, drives tumor progression through a non-cell-autonomous mechanism [125]. Rather than directly promoting the survival of the cancer cell itself, CIN triggers the chronic release of DNA into the cytosol of tumor cells [125]. This cytosolic DNA is sensed by the cGAS-STING pathway, leading to the production of type I interferons and other inflammatory cytokines. Paradoxically, this sustained inflammatory signaling within the TME does not elicit a productive anti-tumor immune response. Instead, it creates a pro-tumorigenic and immunosuppressive niche [125]. The persistent activation of the STING pathway, driven by CIN, does indeed induce apoptosis in T lymphocytes and B lymphocytes [125].This occurs non-cell-autonomously: the tumor cells with CIN activate STING signaling within themselves, leading to the secretion of factors that subsequently trigger the apoptotic death of neighboring immune cells. Specifically, the chronic interferon signaling alters the immune landscape, ultimately leading to the depletion of key anti-tumor immune effectors [125].The apoptosis of T cells and B cells severely compromises the adaptive immune system’s ability to attack the tumor, thereby facilitating immune evasion and promoting cancer progression [125]. In summury, a paradigm wherein CIN promotes tumor aggressiveness not by intrinsically altering cancer cell fitness, but by subverting the TME [125]. The cGAS-STING pathway acts as a crucial mediator in this process, translating genomic instability into an immunosuppressive signal. The induction of apoptosis in T and B cells via this non-cell-autonomous mechanism is a key step that enables immunoevasion and underscores the dual role of inflammatory pathways in cancer, which can be either protective or detrimental depending on context and chronicity [125].

This cell-specific paradox underscores a major limitation of traditional STING agonists and reinforces the unique value of nanomedicine. Nanotechnology offers sophisticated tools to spatially and temporally bias STING activation towards therapeutically favorable compartments. First, nanoplatforms can be engineered for cell-selective delivery. By functionalizing nanoparticles with ligands that target receptors highly expressed on specific cells (e.g., mannose receptors on DCs, or folate receptors on certain cancer cells), the biodistribution of STING agonists can be skewed away from lymphocytes and towards professional antigen-presenting cells and tumor cells [7–9]. Second, nanomaterials enable compartmentalized activation. Strategies that induce STING signaling via endogenous triggers released from specific organelles—such as the mitochondrial DNA (mtDNA) released during nanomedicine-induced cuproptosis—primarily activate the pathway in the cell where the organellar damage occurs (typically the cancer cell). This localizes the initial inflammatory cascade to the tumor bed, potentially sparing circulating lymphocytes from systemic STING activation [17, 103]. Third, stimuli-responsive nanocarriers can control the release of STING agonists based on TME-specific cues (e.g., low pH, high glutathione, specific enzymes). This ensures that pathway activation is concentrated within the tumor mass and its associated immune infiltrate, rather than in peripheral lymphoid organs where it could delete T and B cells [10, 12].

Therefore, the rational design of nanomedicines aimed at the cGAS-STING pathway must go beyond simple delivery enhancement. It should incorporate cell-targeting principles and controlled release mechanisms to choreograph a favorable immunological sequence: (1) preferentially induce immunogenic cell death and STING activation in cancer cells to release tumor antigens and IFN-β; (2) simultaneously deliver agonists to or promote activation in tumor-associated DCs and macrophages to boost their stimulatory capacity; while (3) minimizing off-target, tonic STING signaling in effector T and B cells to preserve their longevity and function. The cuproptosis-mediated strategy detailed in this review, where nanoparticles trigger mtDNA release specifically within cancer cells to act as an in situ STING agonist, exemplifies this sophisticated approach. It initiates the immune cascade precisely at the desired location (the dying tumor cell), generating a local cytokine milieu that recruits and activates immune cells without necessarily inducing cell-intrinsic STING signaling in the infiltrating lymphocytes themselves [104, 106].

In conclusion, acknowledging and addressing the cell-specific duality of STING signaling is paramount for developing effective immunotherapies. Nanomedicine provides a versatile and powerful toolkit to overcome this challenge by enabling precise spatial control over pathway activation. By biasing STING signaling towards tumor cells and antigen-presenting cells while shielding cytotoxic lymphocytes from its deleterious effects, nanoplatforms can strategically harness the full antitumor potential of this pathway, transforming its inherent complexities into a therapeutic advantage.

Conclusions and perspectives

This review has systematically elucidated the emerging paradigm of leveraging nanomedicine to harness the synergistic interplay between cuproptosis and the cGAS -STING pathway for advanced cancer immunotherapy. The central and unifying finding across the surveyed studies is the establishment of a robust mechanistic axis wherein nanomaterial-induced cuproptosis acts as a potent upstream trigger for the activation of the cGAS-STING signaling cascade. The sequence of events is consistently demonstrated: engineered nanoplatforms deliver copper ions or copper ionophores to cancer cells, where they induce the hallmark features of cuproptosis —mitochondrial metabolic disruption, proteotoxic stress through aggregation of lipoylated proteins like DLAT, and destabilization of Fe-S cluster proteins. This specific mitochondrial damage invariably results in the release of mtDNA into the cytosol. The liberated mtDNA is then identified as the critical endogenous ligand that binds to and activates cGAS, initiating the STING-dependent signaling pathway. The subsequent production of type I interferons and pro-inflammatory cytokines orchestrates a comprehensive remodeling of the tumor microenvironment (TME), characterized by dendritic cell maturation, macrophage repolarization towards an anti -tumor phenotype, and robust infiltration of cytotoxic T cells. This coordinated immune activation effectively bridges a unique form of metal-induced regulated cell death with potent innate and adaptive anti-tumor immunity, offering a novel and powerful strategy to overcome the limitations of conventional monotherapies.

Despite the compelling evidence and consistent mechanistic model presented, several critical challenges and unresolved questions remain, which delineate clear avenues for future investigation. A fundamental unknown pertains to the precise biophysical and biochemical mechanisms governing the translocation of mtDNA from the damaged mitochondria into the cytosol; it is unclear whether this process involves the formation of specific pores, mitochondrial permeability transition, BAX/BAK -mediated outer membrane permeabilization, or other unidentified pathways. Elucidating the exact molecular players and dynamics of this crucial step is essential. Furthermore, the long-term efficacy and potential for acquired resistance to this therapeutic approach are not well understood. Cancer cells possess remarkable adaptive capabilities and may develop resistance by downregulating the expression of cuproptosis-susceptible proteins such as FDX1 or lipoylated enzymes, enhancing mechanisms for cytosolic DNA degradation (e.g., via DNases), or evolving strategies to suppress downstream STING signaling. The inherent heterogeneity of the TME also presents a significant hurdle, as variable conditions such as hypoxia, nutrient scarcity, extracellular matrix composition, and the pre-existing immune cell landscape could profoundly influence the efficacy of nanomedicine delivery, cuproptosis induction, and subsequent immune activation, potentially leading to inconsistent therapeutic outcomes across different cancer types and individual patients.

Although the promising preclinical results summarized in this review, significant translational challenges must be acknowledged and overcome before these nanomedicine strategies can benefit patients. A primary gap lies in the fundamental biological differences between mouse models and human cancers, including interspecies variations in immune cell composition, TME features, and metabolic pathways. Nanoplatforms that show excellent efficacy and safety in immunocompromised or syngeneic mouse models may behave differently in humans due to distinct biodistribution patterns, immune recognition, and clearance mechanisms. Moreover, the scalability, reproducibility, and cost-effective manufacturing of complex nanoplatforms under Good Manufacturing Practice (GMP) standards remain formidable hurdles. Long-term toxicity profiles, particularly the potential for off-target copper accumulation in vital organs and the immunogenicity of nanomaterials themselves, require thorough investigation in relevant large animal models and early-phase clinical trials. Finally, patient stratification will be essential; predictive biomarkers—such as baseline expression of cuproptosis-related proteins (e.g., FDX1, DLAT) or activity of the cGAS-STING pathway—need to be identified and validated in human cohorts to select individuals most likely to respond. Addressing these translational gaps through interdisciplinary collaboration among material scientists, immunologists, and clinical oncologists will be crucial for advancing this promising therapeutic paradigm toward clinical reality.

Future research must therefore prioritize several key directions to advance this promising field. First, there is a pressing need to deepen the fundamental understanding of cuproptosis-induced immunogenicity, particularly the detailed cell biology of mtDNA release and its quantitative relationship with cGAS-STING activation. Second, investigating the potential crosstalk and synergy between cuproptosis and other regulated cell death pathways, such as ferroptosis, pyroptosis, and immunogenic apoptosis, could reveal opportunities for designing even more potent multi-modal nanotherapies that trigger parallel immunogenic circuits. From a translational and technological perspective, the development of next-generation, “smarter” nanoplatforms is crucial. These systems should be engineered to dynamically respond to specific tumor microenvironmental cues (e.g., pH, enzymes, redox state) for the precise spatiotemporal control over the release of copper ions and STING agonists, thereby maximizing tumor-specific efficacy while minimizing systemic off-target effects. Concurrently, comprehensive and rigorous assessment of the long-term safety, biodistribution, potential immunotoxicity, and biodegradation profiles of these copper-based and metallic nanomaterials is imperative, requiring studies in more advanced, immunocompetent animal models that faithfully recapitulate the complexity of human cancers and their immune microenvironments. Another critical frontier lies in the identification and validation of predictive biomarkers that can stratify patients most likely to respond to this therapy. Such biomarkers could include the baseline tumor expression levels of key cuproptosis regulators (e.g., FDX1, DLAT), components of the mitochondrial respiratory chain, or proteins within the cGAS-STING pathway, ultimately enabling a personalized medicine approach. Finally, exploring rational combination strategies with established modalities like radiotherapy, chemotherapy, and other immunotherapies (e.g., targeting other immune checkpoints) could unlock synergistic effects and help overcome compensatory resistance mechanisms, paving the way for more durable and effective cancer treatments.

In summary, this review underscores the transformative potential of nanomedicine in strategically coupling cuproptosis with the cGAS-STING pathway to ignite a potent and self-amplifying cycle of anti-tumor immunity. The convergence of nanotechnology, cell biology, and immunology embodied in this approach represents a paradigm shift in cancer therapy. While significant challenges remain, the continued elucidation of underlying mechanisms, coupled with innovations in nanomaterial design and a commitment to translational science, holds immense promise for developing the next generation of effective and personalized cancer immunotherapies. The journey from a compelling mechanistic concept to a clinically viable treatment regimen will require interdisciplinary collaboration, but the path forward is illuminated with remarkable potential.

Abbreviations

CGNPs

Self-accelerating copper-based nanoplatform

cGAS

Cyclic GMP-AMP synthase

cGAMP

2′,3′-cyclic GMP-AMP

CMF IMP

Gelatin methacryloyl xerogel implant co-loaded with Cu0.5Mn2.5O4 nanoparticles and monomethyl fumarate

CMG

Self-amplifying MOF nanoplatform (components: Cu²⁺, Mn²⁺ releasing MOF)

CMCNs@HA

Hyaluronic acid-coated Cu-Mn composite nanoparticles

CLDCu

Inhalable Cu²⁺-chitosan/Disulfiram core-shell nanoparticle

cLipG/CuET

Mitochondria-targeting liposome co-loaded with glycyrrhetinic acid and copper diethyldithiocarbamate

CRT

Calreticulin

CZP NPs

Polydopamine-coated Zinc-Copper bimetallic nanoparticles

DAMPs

Damage-associated molecular patterns

DLAT

Dihydrolipoamide S-acetyltransferase

DSF

Disulfiram

EPR

Enhanced permeability and retention

ER

Endoplasmic reticulum

ES

Elesclomol

ETC

Electron transport chain

FDX1

Ferredoxin 1

GSH

Glutathione

ICB

Immune checkpoint blockade

ICD

Immunogenic cell death

IFN

Interferon

LIAS

Lipoyl synthase

MMF

Monomethyl fumarate

MOF

Metal-organic framework

mtDNA

Mitochondrial DNA

OPMNs-ZCS@siPD-L1

Oxygen pump microneedles loaded with Zinc-doped Copper Sulfide nanoflowers and siPD-L1

OXPHOS

Oxidative phosphorylation

PCM nanoinducer

Cu⁺-loaded metal-phenolic coordination nanoparticle

PDT

Photodynamic therapy

PTMs

Post-translational modifications

PTT

Photothermal therapy

ROS

Reactive oxygen species

RCD

Regulated cell death

SDT

Sonodynamic therapy

STING

Stimulator of interferon genes

TCA cycle

Tricarboxylic acid cycle

TCe6@Cu/TP5 NPs

Brain-targeting copper-coordination nanoassembly loaded with photosensitizer and TP5 peptide

TME

Tumor microenvironment

ZnPT

Zinc pyrithione

Author contributions

CL, YL and WZ designed and conceived the Review. ZJ and YM contributed substantially to discussion of the content. CL and YW wrote the manuscript. ZW and YW generated the figures. ZH edited the manuscript. All authors contributed to reviewing and/or editing of manuscript. All authors approved the final manuscript.

Funding

This work was supported in part by the Beijing Natural Science Foundation (No. 7252174), Wu Jieping Medical Foundation (320.6750.2024-13-59), and Talent development plan for the future in Medical-Engineering Integration by BRA-CDCHE and ZTA (MBRC0012025029).

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All of the authors are aware of and agree to the content of the paper and their being listed as a co-author of the paper.

Competing interests

The authors declare no competing interests.