Apoptosis is conventionally regarded as an immunologically silent RCD mechanism. However, therapeutic strategies like ROS generation can restore tumor immunogenicity through apoptosis induction. When phagocytic capacity is inadequate, apoptotic tumor cells expose and release immune-triggering molecules (e.g., DAMPs, chemokines, cytokines) to activate antitumor immunity. As a redox-active metal, copper induces apoptosis via ROS, DNA damage, and proteasome inhibition, modulating tumor apoptotic sensitivity and immune responses (Xue et al., 2023; Bernal et al., 2025).

The copper (Ⅱ) complex of salicylate phenanthroline induces colorectal cancer cell apoptosis through ROS while enhancing ICD via endoplasmic reticulum (ER) stress and amplified ROS generation (Liu Z. et al., 2023; Chen et al., 2024). Disulfiram (DSF), a copper chelator, synergizes with copper by facilitating intracellular copper transport. DSF/Cu-induced apoptosis transforms dying cancer cells into endogenous vaccines via DAMP release. DSF/Cu sustains high ROS levels, causing persistent oxidative stress, DNA damage, and innate immune activation by downstream apoptotic pathways. DSF/Cu treatment induces apoptosis in breast cancer cells and releases DAMPs, including calreticulin (CRT), high mobility group box 1 (HMGB1), heat shock protein (HSP) 70, and HSP 90 (Guo et al., 2024). ER critically mediates ROS accumulation for immunogenicity restoration. DSF/Cu induces apoptosis and ER stress, upregulating CHOP, Xbp1s, p-EIF2α, and p-IRE1 while enhancing DAMPs release in oral squamous cell carcinoma (Zhao Y. et al., 2024).

By catalyzing •OH generation via single-atom-like form, CuCH-NCs combined with DSF elevate cleaved caspase-3 expression and immunogenicity through CRT/HMGB1/adenosine triphosphate (ATP) upregulation, achieving efficient primary/metastatic tumor suppression in triple-negative breast cancer with anti-programmed death-ligand 1 (PD-L1) therapy (Li et al., 2023). FeCu-DA enables cascade reactions via CAT-like, GSHOx-like, and POD-like activities, continuously generating •OH while depleting GSH. With near-infrared (NIR) irradiation, FeCu-DA downregulates Bcl-2, upregulates Bax, and activates caspase-3 to induce apoptosis, triggering abscopal immunity via DAMP release (Ning et al., 2025). Vitamin K3-loaded copper zinc ferrite nanoparticles (NPs) (Vk3@Si@CuZnIONPs) activate the mitochondrial caspase pathway via ROS, upregulating caspase-3 while eliciting dual immunogenic effects through ROS/heat-mediated HSP70/HSP90 upregulation (Chauhan et al., 2023). GCT NPs promote oxidative stress by GSH depletion and ROS production, inducing mitochondrial dysfunction through Bax/p53/PTEN upregulation and Bcl-2 downregulation. Parallel ER stress enhances immunotherapy by DAMPs release (Guo et al., 2022). Hollow Cu₂MoS₄ NPs elevate caspase-3, cleaved caspase-3, and caspase-8 expression while upregulating p53 and downregulating Bcl-2, inducing apoptosis and CRT exposure (Yao et al., 2024).

Pyroptosis is a gasdermin (GSDM)-mediated RCD characterized by membrane pore formation, cellular swelling, and blebbing. Cleavage of conserved domains in GSDM family members (e.g., GSDMD, GSDME) triggers pyroptosis. Typically, activated caspase-1/4/5/11 cleaves GSDMD, releasing its N-terminal domain to form plasma membrane pores. Under specific conditions, apoptosis-dependent caspase-8 directly cleaves GSDMD. GSDME can be cleaved by caspase-3/8, converting non-inflammatory apoptosis to pyroptosis. This process causes cytoplasmic swelling, membrane rupture, and release of cytoplasmic contents, including DAMPs and pro-inflammatory cytokines, making pyroptosis a critical RCD modality in tumor immune (Tan et al., 2021).

Copper-based nanomedicines induce pyroptosis by promoting ROS production to trigger ER stress and upregulate pyroptosis-related genes. Copper-tannic acid nanoneedle (CuTA) catalyzes a ROS storm in tumor cells with SOD-, CAT-, GSH-Px-, and POD-like activities, causing mitochondrial damage and cytochrome c release to initiate inflammation. These effects activate the inflammasome and caspase-3-mediated GSDME cleavage while releasing DAMPs, effectively activating anti-tumor immunity (Wang et al., 2024a). M-Cu-T depletes GSH by Cu²⁺ to promote ROS accumulation, activating the caspase-3/GSDME cascade and triggering immunogenic pyroptosis via DAMP release (Wang et al., 2023). CP@Gel, a hydrogel-encapsulated self-catalytic nanoplatform, generates ROS via Cu²⁺ catalysis to activate caspase-3/GSDME. This initiates pyroptosis with concurrent release of ATP, HMGB1, interleukin-1β (IL-1β), and interferon-γ (IFN-γ), enhancing tumor immunogenicity and reversing immunosuppressive TIME (Rao et al., 2025). In addition to GSDME-mediated pyroptosis, the Cu-TBB nanomedicine releases Cu⁺ to generate ROS with O₂ as a substrate in tumor cells, activating caspase-1-mediated classical pyroptosis via Gasdermin-D cleavage and promoting release of IL-1β, IL-18, and DAMPs (Zhang Y. et al., 2023).

Ferroptosis is an iron-dependent RCD driven by phospholipid peroxidation and ROS overload, primarily regulated by iron homeostasis and oxidative stress. Iron excess induces ROS generation and activates iron-containing enzymes, leading to subsequent lipid peroxidation. The glutathione peroxidase 4 (GPX4)-dependent system, which relies on solute carrier family 7 member 11 (SLC7A11)-facilitated extracellular cystine uptake, constitutes the basic defense against ferroptosis by utilizing GSH to directly eliminate lipid peroxides (Lei et al., 2024). Dying cells contribute to anti-tumor immunity activation by releasing DAMPs, which modulate the activation of immune cells.

Compared to iron ions, copper-based nanomedicines induce tumor ferroptosis and potent antitumor immune responses through enhanced Fenton-like reactivity and mitochondrial damage. Cu(Ⅱ) complexes disrupt redox homeostasis by GSH depletion and •OH generation, downregulate GPX4 and SLC7A11 expression, and induce ferroptosis with DAMP release (Huang K. B. et al., 2024). Self-assembled copper-alanine NPs (CACG) deplete GSH through reduction from Cu²⁺ to Cu⁺. The resulting Cu⁺ catalyzes H₂O₂ conversion to ROS, downregulates GPX4, and upregulates ACSL4 to trigger ferroptosis. Dying cells upregulate CHOP to induce ER stress and CRT exposure, ultimately activating anti-tumor immunity (Song et al., 2023). Cu²⁺/Cu⁺ in HCuS-PE@TSL-tlyp-1 generates •OH via Fenton reactions, accumulating lipid peroxide to induce ferroptosis and DAMP release (Wang et al., 2024b). FG-CDs@Cu depletes GSH via Cu²⁺, suppresses GPX4 expression, and generates lipid peroxide to drive ferroptosis and CRT translocation (Bao et al., 2023a). Cu_2-xS-GOx@CaCO₃ produces cytotoxic •OH through Cu_2-xS interaction with H₂O₂, synergizing with Ca²⁺ overload to cause mitochondrial dysfunction. This inhibits the GSH/GPX4 axis, accumulating lipid peroxide to induce ferroptosis and DAMP release (Huang et al., 2023). Bimetallic drug-gene co-delivery systems Cu/ZIF-8@U-104@siNFS1-HA and CISAR nanoplatform utilize Cu²⁺/Cu⁺ and Fe³⁺/Fe²⁺ to inhibit the GSH/GPX4 axis, activating immunogenic ferroptosis (Du et al., 2022; Wang Z. et al., 2024). Similarly, CuSe/CoSe₂@syrosingopine (CSC@Syro) employs Cu⁺/Cu²⁺ and Co²⁺/Co³⁺ to suppress GSH/GPX4 and trigger immunogenic ferroptosis (Yang et al., 2023).

In 2022, Tsvetkov et al. discovered that copper binds to lipoylated proteins in the tricarboxylic acid cycle, inducing their aggregation and iron-sulfur cluster loss, which triggers proteotoxic stress and ultimately leads to cuproptosis (Tsvetkov et al., 2022). Key events driving cuproptosis include dysregulated copper transporters, enhanced ionophore-mediated transport, and GSH depletion. These processes collectively elevate intracellular Cu²⁺/Cu⁺ levels, establishing a mechanistic framework for copper-mediated regulation of cell fate. Cuproptosis-related genes comprise two categories: the lipoic acid pathway and the pyruvate dehydrogenase complex (Xie J. et al., 2023). Notably, while oxidative stress from Fenton-like activity of copper is not the initial event of cuproptosis, it actually accelerates the process. Oxidative stress sensitizes cuproptosis by disrupting antioxidant defenses (e.g., GSH depletion), causing mitochondrial dysfunction that impairs ATP-dependent copper transport, and directly damaging copper transporters (Liu et al., 2024a; Vo et al., 2024). Crucially, copper-based nanomedicine-modulated oxidative stress enhances tumor immunogenicity through DAMP release and immune cell stimulation.

MACuS promotes ROS generation via a dynamic reaction between Cu²⁺/Cu⁺ and GSH to intensify cuproptosis and release DAMPs, reprogramming the immunosuppressive TIME (Zu et al., 2024). CEL NPs release Cu²⁺ and ES under NIR-Ⅱ irradiation, inducing cuproptosis through ferredoxin 1 (FDX1) and lipoic acid synthetase (LIAS) downregulation amplified by GSH depletion; toxic aggregation of dihydrollipoamide S-acetyltransferase (DLAT) increases DAMP release to activate anti-tumor immunity (Cheng et al., 2025). Zn-Cu bimetallic nanomedicine CZP NPs provide sustained Cu⁺ to catalyze •OH generation, causing mitochondrial damage and downregulating Fe-S cluster proteins, ultimately releasing mitochondrial DNA (mtDNA) to activate the cGAS-STING pathway and enhance immunotherapy in triple-negative breast cancer. Activation of the cGAS-STING pathway enhances the maturation and activation of antigen-presenting cells by promoting the secretion of cytokines such as type I interferons. STING activation not only stimulates type I interferon secretion through the TBK1/IRF3 axis but also triggers NF-κB activation to regulate PD-L1 expression on tumor cells. The average PD-L1 expression on 4T1 cells treated with CZP NPs was significantly higher than that in the control group (Zhou B. et al., 2025). Similarly, CGNPs utilize Cu²⁺/Cu⁺ to generate ROS, thereby amplifying cuproptosis in triple-negative breast cancer. Mitochondrial disruption leads to the release of mtDNA, which activates the cGAS–STING pathway and promotes the release of DAMPs. The release levels of IFN-β (a representative type I interferon cytokine) and IL-6 were both elevated in the 4T1 cell group treated with CGNPs(Xu et al., 2025). Cu-MOF and Cu-IR783 NPs downregulate LIAS and FDX1 expression while promoting DLAT aggregation to induce cuproptosis. Cu⁺-mediated ROS generation and DAMP release remodel the TIME, enabling primary and metastatic tumor treatment (Hu J. et al., 2024; Cao et al., 2025). Cu/TI mediates cuproptosis via mitochondrial oxidative stress, DLAT aggregation, and FDX1 downregulation, releasing DAMPs to reverse the low immunogenicity of cancer cells (Li et al., 2024c). ECNM disrupts redox homeostasis via GSH depletion and ROS generation, synergizing with FDX1/DLAT suppression-induced cuproptosis to release DAMPs and activate antitumor immunity (Wu et al., 2025). Cu_2-xSe@cMOF releases Cu⁺ to generate ROS and deplete GSH, enhancing cuproptosis and DAMP release, achieving synergistic immunotherapy with anti-PD-L1 (Zhao C. et al., 2024). PCD@CM releases Cu²⁺, which reacts with the excess GSH in the TME, leading to GSH depletion. Meanwhile, Cu⁺-mediated ROS generation amplifies cuproptosis. These mechanisms synergistically promote the release of DAMPs, thereby enhancing the efficacy of anti-PD-L1 therapy (Dai et al., 2024).

ES-Cu-MOF nanomedicine releases Cu²⁺ and ES in fibrosarcoma cells; Elesclomol (ES) shuttles Cu²⁺ to mitochondria, increasing mtROS, reducing DLAT/FDX1 expression, and inducing immunogenic cuproptosis with DAMP release (Luo et al., 2024). PEG@Cu₂O-ES generates abundant ROS to damage ATP-dependent copper transporters (ATP7A/B) on cancer cell membranes, reducing copper efflux to amplify cuproptosis and remodel the TIME for enhanced immunity (Li W. et al., 2024). CLDCu releases DSF and Cu²⁺ to form bis(diethyldithiocarbamate)-copper (CuET), generating excessive ROS that causes mitochondrial damage and ATP depletion to inhibit ATP7B, enhancing Lip-DLAT/DLAT/FDX1 downregulation-mediated cuproptosis with DAMP release (Yan et al., 2024). Similarly, PDA-DTC/Cu NPs release excess Cu²⁺ to produce ROS that disrupts mitochondrial function and limits ATP supply, thereby inhibiting copper transporters ATP7A/B. This process further enhances cuproptosis via DLAT aggregation and Fe-S cluster destabilization, while releasing DAMPs to promote DC maturation and activate infiltrating T cells (Chang et al., 2024). Mito-Jammer decomposes in the acidic TME to release CaO₂ and Cu²⁺; CaO₂-generated H₂O₂ and Ca²⁺ overload intensify Cu²⁺-derived ROS, creating a storm that damages mitochondria and depletes ATP to block Cu-ATPase activity, amplifying cuproptosis and DAMP release (Du C. et al., 2024).

As a newly identified form of RCD, the interplay between cuproptosis and copper-based nanomedicine-modulated oxidative stress warrants further exploration. These innovative strategies for activating anti-tumor immunity offer new insights into the role of copper-dependent redox regulation within TIME.

Extensive molecular crosstalk exists among various RCD forms, with shared upstream signaling pathways or common regulatory molecules determining cell fate through critical molecular switches (He et al., 2024). Within the complex landscape of tumor immunity, multiple RCD modalities may coexist due to the spatiotemporal heterogeneity of the TIME and specific therapeutic interventions (He et al., 2024). This intricate interplay reflects traditional research approaches that categorize cell death into distinct modalities—a simplification that potentially overlooks the reality of cellular states. Beyond established RCD pathways, copper-based nanomedicine-induced oxidative stress critically bridges multiple RCD forms and tumor immunogenic activation.

PANoptosis, an inflammatory RCD pathway involving caspase and RIPK activation, is regulated by the PANoptosome. Zn–CuO₂ NPs disrupt intracellular Cu²⁺/Zn²⁺ homeostasis, leading to abnormal accumulation of metal ions. Cu²⁺ synergizes with Zn²⁺ overload to exacerbate mitochondrial dysfunction through Fenton-like reactions, thereby enhancing ROS accumulation, which accelerates mitochondrial protein/mtDNA release, upregulates Bax, downregulates Bcl-2, and triggers cytochrome c release. Excess Cu²⁺/Zn²⁺ induces mitochondrial damage, dsDNA release, and ER stress, activating AIM2-PANoptosome-mediated PANoptosis and releasing DAMPs to remodel TIME (Hou et al., 2024). Based on the aforementioned findings, copper-based nanomedicine-induced oxidative stress plays a pivotal role in linking multiple RCD modalities with tumor immunogenicity. Notably, such oxidative stress may, in certain contexts, simultaneously activate two or more RCD pathways, thereby enhancing immunogenic responses. With researchers’ talents and efforts, recent advances have demonstrated that the precise coordination of crosstalk among these RCD mechanisms offers new paradigms for restoring tumor immunogenicity.

Given copper’s centrality to cuproptosis, integrating copper-based nanomedicine-induced oxidative stress with other RCD forms has emerged as a main strategy. These nanomedicines disrupt redox homeostasis to induce apoptosis, pyroptosis, or ferroptosis while enabling cuproptosis-centered combinations. PEG-DTPA-SS-CPT releases Cu²⁺, depletes GSH to generate toxic Cu⁺ and ROS, and synergizes with doxorubicin (DOX)/camptothecin to upregulate Bax/cleaved caspase-3 while downregulating Bcl-XL, inducing apoptosis in breast cancer. Copper-driven oxidative stress and GSH depletion further enhance cuproptosis via copper accumulation, releasing DAMPs for antitumor immunity (Wang N. et al., 2024). BCO-V_Cu triggers ROS bursts to upregulate Bax and downregulate Bcl-2, inducing apoptosis, while its ferroelectric properties enhance Cu²⁺ release/aggregation through membrane permeability alterations; Cu²⁺ accumulation downregulates FDX1/LIAS, promoting DLAT oligomerization and cuproptosis, ultimately enhancing DAMP release and immune activation (Du Y. et al., 2024). FA-PZ@MOF NPs promote the accumulation of Zn²⁺ and Cu⁺, exacerbating ROS storms and mitochondrial damage. This leads to lipoylated protein aggregation, Fe–S cluster loss, and the induction of cuproptosis. Meanwhile, ROS and Polyphyllin Ⅵ act synergistically to activate the NLRP3 inflammasome, recruit caspase-1, and cleave GSDMD, thereby triggering pyroptosis. The enhanced interplay between cuproptosis and pyroptosis promotes the release of DAMPs and anti-tumor immunity (Yi et al., 2025). F127 MOF-199 induces cuproptosis via copper overload, while in situ sulfidation converts it to Cu_2-xS NPs, activating photothermal therapy (PTT)/chemodynamic therapy (CDT) to release cytochrome c, activate caspase-3, and cleave GSDME for pyroptosis, culminating in DAMP release (Xiao W. et al., 2024).

The combination of ferroptosis and cuproptosis strategies further highlights the pivotal role of copper-based nanomedicines in tumor immune regulation. Cu-DBCO/CL nanozymes generate ROS storms through POD-like activity, leading to GSH/GPX4 depletion, lipid peroxidation, and ferroptosis. Simultaneously, mitochondrial dysfunction reduces ATP levels, impairing ATP7A-mediated copper efflux and resulting in intracellular Cu⁺ accumulation. The trapped Cu⁺ promotes DLAT oligomerization and downregulation of LIAS, thereby promoting cancer cell death and facilitating the release of DAMPs and TAAs (Liu et al., 2024c). Moreover, oxidative stress modulated by copper-based nanomedicines may induce the interplay among three distinct forms of RCD within tumor cells. NSeMON-P@CuT/LipD releases copper, which induces DLAT aggregation and Fe–S cluster loss, thereby triggering cuproptosis. Concurrently, Cu²⁺/Cu⁺ depletes GSH and generates •OH, inducing ferroptosis through the GSH/GPX4 pathway. The resulting oxidative stress further amplifies cuproptosis by exacerbating mitochondrial dysfunction and inhibiting ATP7B-mediated copper efflux. In addition, pemetrexed acts synergistically with •OH to induce apoptosis (Zhang M. et al., 2025). These coordinated RCD cascades release DAMPs to activate antitumor immunity (Luo et al., 2025).

Despite much progress, the detailed molecular mechanisms by which copper-based nanomedicines modulate oxidative stress across various RCD modalities remain incompletely understood, particularly with regard to copper’s unique biological roles. The potential impact of copper-based nanomedicine-modulated oxidative stress on other forms of RCD, such as necroptosis and secondary necrosis, calls for further exploration. Progress in these areas will provide deep insights into copper-driven ICD and support the development of advanced cancer immunotherapies (Liu et al., 2024b).

Copper ionophores, such as ES and DSF, have been applied for Cu²⁺ delivery in tumor immunotherapy. ES stands out for its exceptional transport rate and selective mitochondrial copper delivery. Nanomedicine encapsulation of ES-Cu complexes enhances circulatory stability and tumor targeting of ES. For instance, ECNM employs a ROS-responsive polymer to encapsulate ES-Cu, prolonging systemic circulation and boosting tumor accumulation. Subsequently, released ES and Cu²⁺ synergize with cinnamaldehyde to disrupt redox homeostasis, inducing cuproptosis and DAMP release, thereby achieving immunotherapy (Table 1) (Wu et al., 2025). Similarly, TSF@ES-Cu NPs generate abundant ROS, disrupt copper homeostasis, induce cuproptosis, and facilitate the release of DAMPs. These effects collectively promote DCs maturation, enhance CD8⁺ T-cell infiltration, and reduce M2 tumor-associated macrophages (TAMs), thereby enhancing anti-tumor immune responses (Table 1) (Gao et al., 2025). PEG@Cu₂O-ES passively targets breast cancer via the enhanced permeability and retention (EPR) effect, releasing ES and Cu₂O. ROS derived from Cu₂O attack ATP-dependent copper transporters on cancer cell membranes, reducing Cu²⁺ efflux, while free ES boosts Cu²⁺ influx, synergistically amplifying cuproptosis. Additionally, Cu²⁺ upregulates PD-L1 expression, sensitizing tumors to anti-programmed cell death protein 1 (PD-1) immunotherapy (Table 1) (Li W. et al., 2024).

DSF, an FDA-approved anti-alcoholism agent, exerts antitumor effects primarily through ROS modulation, with its efficacy dependent on copper. In vivo, DSF metabolizes into diethyldithiocarbamate (DTC), which chelates Cu²⁺ to form the cytotoxic complex Cu(DTC)₂. Co-delivering DSF, DDC, or DSF prodrugs with copper markedly enhances bioavailability and therapeutic potency of copper-based nanomedicines (Chen et al., 2022; Chang et al., 2024). CuCH-NCs/DSF releases Cu²⁺ to modulate oxidative stress, which subsequently complexes in situ with DSF to form the highly cytotoxic compound Cu(DTC)₂. This process induces robust cuproptosis, upregulates PD-L1 expression, and promotes the release of DAMPs, thereby synergizing with anti-PD-L1 immunotherapy to enhance anti-tumor immunity (Table 1) (Li et al., 2023). Alb/LF NPs encapsulating DDC/Cu-Fe facilitate brain accumulation, where DDC/Cu-Fe cooperatively induces glioma cell ferroptosis through oxidative stress, activates T cell immunity, and suppresses TAMs by FROUNT (also known as NUP85) inhibition (Table 1) (Wang R. et al., 2024). PDA-DTC/Cu NPs efficiently deliver Cu²⁺ for intracellular accumulation by employing polydopamine-coated nanocarriers, releasing DTC and Cu²⁺ within tumors via the EPR effect. These NPs promote cuproptosis through ROS generation and copper overload, leading to DAMP release that promotes DC maturation and T-cell activation. Meanwhile, generated ROS reprograms TAMs toward anti-tumor phenotype (Table 1) (Chang et al., 2024).

Anthracycline chemotherapeutics are extensively proven to alleviate tumor-induced immunosuppression and activate antitumor immunity. Copper-based nanomedicine co-delivery strategies with anthracycline chemotherapeutics not only reduce off-target toxicity but also enhance tumor cell eradication through immunogenic activation. DOX initiates mitochondrial damage by binding to cardiolipin on inner mitochondrial membranes, generating ROS that synergize with oxidative stress modulated by copper-based nanomedicine for immunotherapy. In PCD@CM, Cu²⁺ and DOX are co-delivered via a homologous targeting strategy enabled by tumor cell membrane encapsulation. Upon GSH-mediated reduction of Cu²⁺ to Cu⁺, PCD@CM undergoes responsive disassembly, releasing Pdots and DOX. The released Cu⁺ not only catalyzes the Fenton-like reaction with endogenous H₂O₂ to generate •OH, inducing intracellular oxidative stress, but also triggers cuproptosis. Furthermore, the synergistic effect of NIR-Ⅱ PTT, chemotherapy, and cuproptosis promotes the release of DAMPs and TAAs, thereby initiating a potent antitumor immune response through DC maturation (Table 1) (Dai et al., 2024). In particular, the anthracycline derivative mitoxantrone (MTO) exhibits exceptional photothermal conversion capabilities. M/A@MOF@CM NPs, comprising copper-based metal-organic frameworks (MOF) loaded with MTO and axitinib, induce ferroptosis through copper-modulated oxidative stress. This system disrupts copper homeostasis by impairing ATP production, thereby increasing cytoplasmic Cu²⁺ levels and initiating cuproptosis. Simultaneously, the released MTO exerts both chemotherapeutic and PTT effects. M/A@MOF@CM effectively promotes cancer cell death and DAMP release, contributing to the reprogramming of the immunosuppressive TIME (Table 1) (Ji et al., 2024).

Tumor cells exhibit hyperactive metabolism compared to normal cells, leading to metabolic waste accumulation and acidic pH in the TME. This metabolic heterogeneity not only supports tumor proliferation but also facilitates immune evasion. Combining copper-based nanomedicines with metabolic intervention drugs effectively reverses immunosuppressive TIME.

Indoleamine 2,3-dioxygenase 1 (IDO 1)-driven tryptophan catabolism via the kynurenine pathway creates an immunosuppressive environment that facilitates immune evasion and promotes tumor progression. In PdPtCu/NLG919@BSA-Ce6/T^ER, the IDO inhibitor NLG919 blocks the tryptophan/kynurenine immune escape axis, enhancing effector T-cell function while suppressing regulatory T-cells, thereby amplifying tumor-specific immunity induced by PdPtCu-modulated oxidative stress (Table 1) (Xie Y. et al., 2023). CuSe/CoSe₂@syrosingopine downregulates monocarboxylate transporter 4 (MCT4) to modulate lactate metabolism in cancer cells. This acidifies the intracellular milieu, enhancing Cu⁺/Cu²⁺ and Co²⁺/Co³⁺ catalytic ROS generation to induce ferroptosis, while neutralizing acidic TME to alleviate immunosuppression (Table 1) (Yang et al., 2023). Cu-DBCO/CL co-delivers cholesterol oxidase (CHO) and the lysyl oxidase inhibitor LOX-IN-3. Benefiting from its enzyme-like activity, Cu-DBCO/CL catalyzes O₂ and H₂O₂ into O₂ ⁻• and •OH, promoting both cuproptosis and ferroptosis. ROS-triggered release of LOX-IN-3 inhibits lysyl oxidase activity, remodeling the extracellular matrix, and enhancing CD8⁺ T cell infiltration. Furthermore, CHO-induced cholesterol depletion not only amplifies •OH generation but also downregulates immune checkpoints PD-1 and TIM-3, thereby restoring CD8⁺ T-cell antitumor activity (Table 1) (Liu et al., 2024c). BPTES, a selective glutaminase (GLS1) inhibitor, suppresses GSH synthesis. Platelet membrane-coated PCB delivers BPTES to tumors, where it inhibits GLS expression and depletes GSH, promoting cuproptosis and copper-mediated ROS production. This dual mechanism triggers tumor cell death and DAMP release, increasing mature DCs and CD8⁺ T cell infiltration (Table 1) (Zhang et al., 2024). LipoCu-OA/ACF, co-assembled from copper oleate and the HIF-1α inhibitor acriflavine (ACF), releases Cu²⁺ to activate immune responses through oxidative stress. Simultaneously, ACF depletes GSH, inhibiting HIF-1α signaling and amplifying oxidative stress. Beyond HIF-1α suppression, ACF alleviates immunosuppression by reducing extracellular lactate and adenosine levels, as well as downregulating PD-L1 expression (Table 1) (Zhang X. et al., 2023). Pic, an arginase 2 (Arg2) inhibitor, targets mitochondrial Arg2 to disrupt polyamine synthesis. Cu-Pic/HA NPs generate ROS via multiple enzyme-like activities while depleting intracellular polyamines. Released Cu²⁺ induces lysosomal disruption, inactivating the polyamine transporter ATP13A2 on lysosomal membranes and blocking polyamine uptake. Meanwhile, Pic inhibits Arg2 activity, halting upstream polyamine synthesis and promoting mitochondrial ROS accumulation. The effective synergy between pyroptosis and cuproptosis triggers DAMP release, activating anti-tumor immunity (Table 1) (Zhu et al., 2024).

To enhance the efficacy of oxidative stress modulated by copper-based nanomedicines in activating tumor immunity, researchers co-deliver nanomedicines with immunotherapeutic agents such as Toll-like receptor (TLR) agonists. The TLR7/8 agonist resiquimod (R848) primarily targets antigen-presenting cells like DCs, promoting the secretion of pro-inflammatory cytokines and improving antigen-presenting cell polarization/maturation to initiate T-cell responses. Although TLR agonists contribute to remodeling the TIME, their toxicity due to excessive cytokine production remains a concern. Nanoplatforms integrating TLR agonists with copper-based nanomedicines effectively reduce off-target toxicity while amplifying oxidative stress-modulated immunogenic activation.

CMO-R@4T1 utilizes Cu-MoO_x nanozymes to generate ROS and disrupt antioxidant defenses, causing oxidative damage to tumor cells and releasing DAMPs and TAAs. Released R848 triggers immune activation, synergistically eliminating tumors and establishing long-term immune memory (Table 1) (Jana et al., 2024). Toyocamycin amplifies ER stress by targeting the IRE1α–X–box binding protein 1 (XBP1) pathway. In GCT NPs co-loaded with 1G₃-Cu and toyocamycin, 1G₃-Cu-induced mitochondrial dysfunction synergizes with toyocamycin-mediated ER stress to drive tumor cell apoptosis and DAMPs release, effectively inhibiting tumor growth, promoting DC maturation, and increasing CTL infiltration (Table 1) (Guo et al., 2022). Polyphyllin I reverses immunosuppression by activating the cGAS–STING pathway. S@Cu-MOF/PPI delivers Polyphyllin I with reduced toxicity; released Cu²⁺ triggers mitochondrial dysfunction and cuproptosis. ROS generation and mtDNA release synergize with Polyphyllin I to activate the cGAS/STING pathway, enhancing anti-tumor immunity (Table 1) (Xu et al., 2024). Additionally, co-delivery of other immunostimulatory metal ions (e.g., Zn²⁺, Mn²⁺) with copper-based nanomedicines can further enhance innate immune responses by activating the cGAS–STING signaling pathway (Li Q. et al., 2025; Liu et al., 2025; Zhou B. et al., 2025).

The insufficient intracellular H₂O₂ levels and weakly acidic environment within tumor cells are major limiting factors for ROS generation by copper-based nanomedicines, resulting in immune activation that is insufficient for therapeutic efficacy. Within this complex TIME, increasing the concentration of the catalytic substrate H₂O₂ and enhancing acidity are the primary strategies for improving the overall efficiency of Fenton-like reactions. Specifically, elevating H₂O₂ concentration can be achieved through increasing its supply and reducing its consumption, while strengthening the acidic environment can be realized by boosting the levels of acidic substances within the TIME. Approaches to increase H₂O₂ supply include exogenous H₂O₂ delivery and in situ catalytic generation via enzymatic reactions. Strategies to reduce H₂O₂ consumption involve depleting GSH to minimize H₂O₂ loss and inhibiting its decomposition.

Currently, achieving satisfactory cancer immunotherapy using CDT based solely on Fenton-like reactions is challenging. External energy fields, including NIR light, ultrasound, magnetic fields, and microwaves, enhance the efficiency of copper-based nanomedicines in generating ROS for immune activation by directly converting external physical stimuli into chemical energy or indirectly augmenting Fenton-like reactions through heat generation (Figure 2). Compared to optimizing the endogenous reaction environment, utilizing external physical fields as remote or wireless energy sources allows for precise control over the progression and intensity of catalytic reactions, achieving a high degree of spatiotemporal controllability and tunable catalytic performance. Immunotherapy employing copper-based nanomedicines driven by external energy fields exhibits high selectivity, efficiency, and low side effects, making it a highly active research area in current tumor immunotherapy.