The classical Fenton reaction is a complex reaction system catalyzed by Fe²⁺, primarily consisting of three stages: chain initiation, chain propagation, and chain termination. At the heart of this reaction are two key chemical steps^[15], as shown in Equations (1) and (2). First, Fe²⁺ catalyzes the generation of •OH from H₂O₂, while being oxidized to Fe³⁺ itself (Equation 1). Subsequently, Fe³⁺ reacts with H₂O₂ to regenerate Fe²⁺ (Equation 2), thus entering the next reaction cycle^[16]. However, it is worth noting that the form and reactivity of iron are closely related to the concentration of H₂O₂ and the pH value in the system. This reaction requires a large amount of H₂O₂, and the reaction system can only achieve optimal conditions when the pH is around 3^[17]. When the pH exceeds 3, iron hydroxide precipitates tend to form; at a pH of 4, the amount of iron hydroxide reaches its peak, and at this point, the activity of iron hydroxide is significantly higher than that of Fe²⁺, thereby markedly inhibiting the reaction rate^[18]. Furthermore, compared to Equation (1), the reaction rate of Equation (2) is slower, limiting the regeneration process of Fe^2+[19]. To lower the pH of the tumor microenvironment, Chen et al.^[20] constructed amorphous nanoparticles loaded with carbonic anhydrase inhibitors (AFeNPs@CAI). Through the action of CAI, these nanoparticles can inhibit the overexpression of carbonic anhydrase in tumor cells, reducing the intracellular pH and thereby enhancing the Fenton reaction mediated by AFeNPs and intensifying intracellular oxidative stress, ultimately promoting cell apoptosis (Figure 1). Additionally, Wang et al.^[21] found that ferritin heavy chain can convert Fe²⁺ into Fe³⁺ and encapsulate it within ferritin, resulting in less-than-ideal therapeutic effects for Fe-based CDT. They synthesized pH-responsive small interfering RNA (siRNA)-encapsulated Fe⁰ nanoparticles (Fe⁰-siRNA NPs). In this design, upon entering cancer cells, the pH-responsive Fe⁰-siRNA NPs gradually dissociate, releasing Fe²⁺ and siRNA. The release of siRNA leads to downregulation of ferritin heavy chain, thereby increasing the accumulation of Fe²⁺ in tumor cells. This process promotes a more efficient Fenton reaction within tumor cells, enhancing the chemodynamic reaction rate.

Similar to iron ions, copper ions also possess redox properties, enabling them to react with H₂O₂to produce •OH^[22]. The steps of the copper-ion-mediated Fenton-like reaction are shown in Equations (3) and (4). First, Cu²⁺is reduced to Cu⁺via electron transfer, after which Cu⁺acts as a catalyst to react with H₂O₂and generate •OH. Cu⁺can then react again with H₂O₂, forming a catalytic cycle. Under the catalytic action of copper ions, the application scope of the Fenton-like reaction is extremely broad. Within a pH range of 3 to 7, copper ions exhibit high catalytic efficiency, even 160 times faster than that catalyzed by Fe^2+[23]. Additionally, Cu⁺can undergo redox reactions with the reducing agent GSH present in tumor cells, further damaging these cells. By adjusting conditions such as copper ion concentration, H₂O₂concentration, and pH, the reaction rate and product generation can be effectively controlled, thereby enhancing its application efficacy in tumor treatment^[24]. Tang et al.^[25]described a novel mesoporous silica nanoparticle (MSN) loaded internally with the chemotherapeutic drug doxorubicin (DOX) and surface-modified with a copper peroxide (CuO₂) catalyst to block the pores and prevent premature drug release. Under stimulation from the tumor microenvironment, CuO₂decomposes, generating exogenous H₂O₂and Cu²⁺, where Cu²⁺consumes intracellular glutathione to produce Cu⁺. Cu⁺effectively catalyzes the production of highly cytotoxic •OH from exogenous H₂O₂, synergistically working with DOX to achieve combined chemodynamic therapy and chemotherapy, thus improving the therapeutic effect on tumors. Metal-organic framework (MOF)-based nanomaterials are formed through coordination bonds between metal ions and organic ligands. Due to their tunable structure, high porosity, ease of functionalization, and responsiveness to stimuli, MOFs demonstrate great application potential in the biological field^[26]. Based on this, Wang et al.^[27]successfully prepared Cu²⁺-doped ZIF-8 metal-organic framework (Cu²⁺/ZIF-8) using ion doping technology. Furthermore, DOX was used as a model chemotherapeutic drug and loaded into Cu²⁺/ZIF-8 via coordination with metal ions. Subsequently, polydopamine (PDA) was further surface-modified to obtain the DOX@Cu²⁺/ZIF-8@PDA nanocomposite (DCZP). In the weakly acidic tumor microenvironment, DCZP is degraded, releasing DOX and Cu²⁺. Following irradiation with an 808 nm laser, the heat generated by PDA can effectively kill tumor cells and promote DOX release. The released Cu²⁺can deplete intracellular GSH, disrupt redox balance, and increase intracellular Cu⁺concentration, thereby effectively inhibiting tumor growth in vivo through CDT.

Manganese dioxide (MnO₂) can react with H₂O₂ to produce •OH and O₂, thereby improving the hypoxic tumor microenvironment. This process is the core step of the MnO₂-mediated Fenton-like reaction. Additionally, MnO₂ can also react with GSH, further enhancing oxidative stress in tumors. The relevant reactions are shown in equations (5) to (8). During the regulation of CDT, manganese typically functions in its divalent state. In the presence of HCO₃^-, Mn²⁺ reacts with H₂O₂ to generate •OH and is subsequently converted into Mn^4+[28]. Its catalytic efficiency is similar to that of iron, but manganese has poor stability in environments with a pH above 4. Moreover, the Mn²⁺ produced during the above reaction serves as an excellent magnetic resonance imaging (MRI) agent^[29], facilitating the construction of integrated diagnostic and therapeutic nanoplatforms. In summary, the MnO₂-mediated Fenton-like reaction plays an important role in improving the hypoxic tumor microenvironment, weakening the tumor's antioxidant capacity, and directly oxidizing and killing tumor cells by generating O₂, consuming GSH, and producing highly oxidative •OH. These reaction steps provide a clear mechanistic basis for the application of MnO₂ in tumor therapy and lay the foundation for regulating the tumor microenvironment and enhancing therapeutic efficacy. Based on this research background, Fu et al.^[30] employed an in situ biomimetic mineralization method, using manganese-doped calcium phosphate (MnCaP) to mineralize glucose oxidase (GOx), successfully synthesizing spherical nanoparticles (GOx-MnCaP NPs). Subsequently, researchers loaded DOX onto these nanoparticles, constructing a TME-responsive GOx-MnCaP-DOX nanoplatform. Once this nanoplatform enters tumor cells, Mn²⁺, GOx, and DOX are sequentially released. Mn²⁺ reacts with HCO₃^- to generate •OH, which synergizes with GOx and DOX to effectively kill tumor cells (Figure 2). Xu et al.^[31] developed a nano-liposome (Mn-MK3@LP) encapsulating manganese and menadione (MK3) for hepatocellular carcinoma. After tumor cells uptake this nano-liposome, MK3 and manganese ions are released. MK3 increases the concentration of H₂O₂ in the tumor microenvironment, while Mn⁵⁺ and Mn⁷⁺ consume excess GSH in the TME, generating Mn²⁺. Mn²⁺ reacts with H₂O₂ to produce •OH, ultimately inducing tumor cell apoptosis.

Calcium ions play an indispensable and crucial role in various physiological activities of the body. They not only maintain the bioelectrical potential of cell membranes but also regulate the normal contraction and relaxation functions of muscles^[32]. However, in tumor cells, elevated levels of •OH can disrupt the normal metabolism of calcium ions, leading to abnormal calcium accumulation. CaO₂exhibits good stability in tumor cells, not reacting with hydrogen peroxide but instead reacting with water to release O₂, H₂O₂, and Ca(OH)₂. The released Ca(OH)₂can increase the local pH, thereby alleviating the acidic microenvironment of tumors, inhibiting tumor growth, and enhancing the effectiveness of other therapeutic approaches. Increased calcium ion concentration can cause calcium overload in tumor cells, ultimately inducing tumor cell apoptosis^[33]. In summary, CaO₂can efficiently react under neutral or weakly acidic conditions, adapting to the acidic microenvironment of tumors, providing O₂and H₂O₂while simultaneously regulating the acidic environment. The Fenton-like reaction equations involving calcium ions are shown in Equations (9) and (10). Chen et al.^[12]encapsulated polyphenolic compound tannic acid (TA) and Fe³⁺on the surface of CaO₂nanosphere aggregates, forming a novel nanosystem for enhancing tumor chemodynamic therapy (CaO₂@TA-Fe³⁺). Studies have found that when this nanosystem enters the tumor site, CaO₂decomposes within tumor cells to produce H₂O₂, while TA rapidly reduces Fe³⁺to Fe²⁺. Additionally, the •OH generated during the Fenton reaction can induce oxidative stress in tumor cells, promoting the "calcium overload" process and accelerating tumor cell apoptosis (Figure 3).

Ruthenium, a relatively inexpensive precious metal, possesses a low redox potential and can efficiently catalyze the decomposition of H₂O₂, generating •OH. Its catalytic activity is particularly pronounced under neutral to weakly acidic conditions^[34]. Furthermore, ruthenium ions can be combined with nanocarriers to enhance targeting capabilities and synergize with other therapeutic approaches. This makes ruthenium highly valuable for research and application in fields such as cancer treatment, pollution control, and energy catalysis. Yang et al.^[35] utilized ruthenium metal to design and construct an ultrathin two-dimensional RuCu nanosheet-based nanoenzyme, with the Fenton-like reaction equations of RuCu shown in Equations (11) to (15). This nanoenzyme features a large specific surface area, abundant pores, and defect structures, enabling it to efficiently promote the Fenton reaction even in tumor microenvironments with suboptimal H₂O₂ concentrations and pH levels. Additionally, RuCu nanosheets exhibit high superoxide dismutase-like activity and glutathione (GSH) consumption capacity, accelerating the production of H₂O₂ and inhibiting GSH's scavenging effect on H₂O₂, thereby increasing intratumoral H₂O₂ levels. Consequently, RuCu nanosheets demonstrate specific cytotoxicity against tumor cells and the ability to suppress tumor growth, making them promising candidates for CDT.

PTT refers to a cancer treatment method that uses photothermal agents to convert light energy into heat under near-infrared (NIR) laser irradiation, thereby increasing the temperature of tumor tissues and inducing cell apoptosis. PTT has advantages such as high selectivity, minimal invasiveness, low toxicity, deep tissue penetration, and high spatial resolution, bringing new therapeutic approaches and hope for cancer treatment. However, the PTT treatment process heavily relies on high-energy light sources, yet light penetration depth is limited, making it difficult to completely eliminate tumor cells with photothermal therapy alone. During CDT treatment, the elevated temperature in the tumor microenvironment accelerates the rate of Fenton catalytic reactions. Therefore, researchers have proposed combining PTT with CDT to achieve enhanced antitumor therapeutic effects^[38]. In the combined PTT and CDT treatment, PTT locally elevates the temperature, accelerating the Fenton/modified Fenton reactions in CDT, promoting the decomposition of H₂O₂to generate more •OH and weakening its antioxidant capacity. The ROS produced by CDT disrupts cellular heat shock proteins (HSPs) through oxidative stress, enhancing the thermal effect of PTT. Additionally, ROS induces lipid peroxidation, DNA damage, and protein denaturation, promoting tumor cell apoptosis, ferroptosis, and immunogenic cell death (ICD), effectively killing tumor cells in deep regions and compensating for the limited light penetration depth of PTT^[39]. From the perspective of cellular signaling pathways, the combined treatment activates oxidative stress-related pathways (such as NF-κB, p53, MAPK) and inhibits antioxidant pathways (such as Nrf2), while releasing danger signals (such as ATP and HMGB1) through ROS and high temperatures, thereby enhancing the antitumor immune response^[40]. This combination therapy overcomes the limitations of single therapies in terms of insufficient H₂O₂supply, hypoxia in the tumor microenvironment, heat tolerance, and inadequate deep-tissue killing ability, while reducing toxic side effects and improving treatment efficiency and precision, demonstrating great potential in tumor treatment^[41]. Therefore, the combined PTT/CDT therapy has received widespread attention in recent years.

It is well known that NIR light can be divided into two distinct ranges: near-infrared region I (NIR-I, 700~900 nm) and near-infrared region II (NIR-II, 1000~1700 nm)^[42]. Among these, research on NIR-I has started earlier and progressed more deeply compared to NIR-II. For instance, Chen et al.^[43]developed a simple pH- and NIR-responsive microneedle system using biocompatible polyvinylpyrrolidone (PVP) as a matrix and PVP-stabilized CuO₂ nanoparticles (CuO₂ NPs) as therapeutic agents for efficient anti-melanoma treatment. After reaching the melanoma site, this microneedle system releases CuO₂ NPs, which on one hand consume endogenous GSH in tumor cells, and on the other hand dissociate into Cu²⁺ and H₂O₂. Cu²⁺ reacts with endogenous H₂O₂to generate •OH, which is harmful to tumor cells, and the self-supplied H₂O₂can also promote the production of •OH. Additionally, due to the aggregation of CuO₂ NPs, the microneedle system exhibits excellent photothermal performance, achieving significant NIR-mediated temperature elevation in the melanoma region in vivo. In vivo experiments on mice demonstrated that the combined CDT and PTT tumor treatment strategy exhibited outstanding cell-killing and tumor-removal effects in the melanoma area. Cheng et al.^[44]synthesized iron-rich mesoporous polydopamine via a one-pot method, coated it externally with polyethylene glycol (PEG), and finally combined it with GOx to form a nanocomposite material (GPM@Fe). When these nanoparticles reach the tumor site, Fe²⁺ and GOx dissociate from the nanoparticles. Fe²⁺ reacts with intracellular H₂O₂in tumor cells to produce Fe³⁺ and •OH, and Fe³⁺ further reacts with intracellular GSH to generate Fe²⁺ and oxidized glutathione (GSSG), forming a cascade catalytic reaction. GOx can catalyze glucose to produce H₂O₂ and gluconic acid, further enhancing the production of •OH. Moreover, the excellent photothermal conversion performance of mesoporous polydopamine allows it to convert light energy into heat, raising the temperature at the tumor site and promoting GOx's catalytic efficiency and GSH consumption. In vitro and in vivo antitumor experiments showed that these nanoparticles, with their dual GSH-consuming function, possess certain tumor-targeting capabilities and exhibit low toxicity in vivo, effectively killing tumor cells. Wang et al.^[45]constructed a hollow Cu₉S₈nanomaterial. Compared to solid Cu₉S₈particles, the hollow Cu₉S₈nanoparticles significantly increased the specific surface area, greatly boosting the number of active sites available for catalyzing Fenton-like reactions. Furthermore, the hollow Cu₉S₈particles also demonstrated excellent photothermal properties, accelerating the generation of •OH in Fenton reactions. After entering tumor cells, under 808 nm near-infrared light irradiation, the rate at which copper ions react with H₂O₂ to produce •OH significantly increases, thereby inducing tumor cell death. In vivo experiments on mice showed that the hollow Cu₉S₈nanoparticles, due to their abundant active sites and superior photothermal performance, exhibited good photoacoustic imaging effects and outstanding chemodynamic therapy outcomes.

Although researchers have made significant progress in NIR-I light-mediated photothermal therapy, the penetration depth of NIR-I light still fails to meet the ideal requirements for tumor treatment. In contrast, researchers have found that NIR-Ⅱ light not only has a deeper penetration depth^[46]but also exhibits stronger photothermal conversion efficiency. When NIR-Ⅱ light-guided PTT is combined with CDT, the temperature at the irradiated tumor site rapidly increases, accelerating the generation of •OH in the Fenton/modified Fenton reaction, enhancing the regeneration cycle of Fenton/modified Fenton particles, and regulating the pH of the TME^[47]. Therefore, researchers have conducted a series of studies on NIR-Ⅱ-mediated combined PTT/CDT therapy. Zhou et al.^[48]prepared a biodegradable Cu_{2- x}Te nanosheet (bioCu_{2- x}Te NSs), which exhibits excellent NIR-Ⅱ photothermal conversion performance. In vivo studies using a breast cancer mouse model demonstrated that bioCu_{2- x}Te NSs exhibited outstanding antitumor efficacy under NIR-Ⅱ light irradiation. Zhang et al.^[49]encapsulated Fe³⁺within a three-dimensional metal-polyphenol network formed by coordinating Aza-BODIPY-modified catechol-functionalized boron nitride with F127 via multi-dentate metal ligands, yielding ABFe NPs. Due to metal-ligand coordination, these nanoparticles exhibit strong absorption in the NIR-Ⅱ range, enhancing their photothermal conversion efficiency under NIR-Ⅱ laser irradiation. Both in vitro and in vivo experiments confirmed that ABFe NPs possess good biocompatibility and photoacoustic imaging capabilities. Under photoacoustic imaging guidance, enhanced PTT combined with CDT effectively inhibited 4T1 tumor growth (Figure 4). Ou et al.^[50]successfully synthesized BDP-4OH by coupling 3,4-dihydroxybenzaldehyde with boron difluoride dipyrrylmethane (BODIPY), shifting its spectral characteristics into the NIR-Ⅱ region. Subsequently, they chelated Fe³⁺with BDP-4OH to form topologically structured BDP-Fe nanoparticles. After entering tumor cells, these nanoparticles exhibited strong photoacoustic imaging capability under NIR-Ⅱ light irradiation. Meanwhile, BDP-Fe nanoparticles generated •OH through the Fenton reaction, synergistically killing tumor cells with PTT. Liu et al.^[51]reported a molybdenum-based polyoxometalate derived from molybdenum carbide (Mo₂C) as a PTT/CDT nanomedicine. The molybdenum-based polyoxometalate clusters can self-assemble into nanomedicines under weakly acidic conditions, rapidly accumulating in tumor cells via the enhanced permeability and retention (EPR) effect, demonstrating excellent tumor-targeting ability. Under NIR-Ⅱ light irradiation, the nanomedicine exhibits outstanding photoacoustic imaging and photothermal conversion capabilities. In vivo experiments confirmed that the photothermal effect of the nanomedicine significantly enhances the antitumor efficacy of CDT, showcasing great potential for clinical applications.

In summary, CDT nanomedicines with photothermal effects have enhanced the efficacy of CDT to some extent. However, for tumors located in deep tissues, this approach is limited by the penetration depth of lasers, and there are still certain shortcomings in treatment outcomes. Nevertheless, with the introduction of more NIR-II materials and the development of CDT nanomedicines featuring stronger photothermal properties, PTT/CDT combination therapy will have greater potential for application in tumor treatment.

Chemotherapy refers to the use of drugs to kill tumors. Currently, in clinical practice, chemotherapy remains one of the primary methods for cancer treatment^[52]. Chemotherapy can eliminate residual lesions that cannot be treated by surgical resection or radiotherapy, and its high toxicity also limits tumor growth and metastasis, thereby extending patients' survival time. However, chemotherapy has significant side effects on the human body and can easily lead to drug resistance, which is detrimental to the long-term treatment of tumors. To address these issues, researchers have turned their attention to the combined treatment of chemotherapy and CDT. The combination of CDT and chemotherapy leverages the synergistic effect between reactive oxygen species (ROS) generated by CDT and the direct cytotoxicity of chemotherapy drugs, significantly enhancing DNA damage and lipid peroxidation in tumor cells. DNA damage induced by chemotherapy drugs activates the p53 pathway^[53] and cell cycle arrest mechanisms, further amplifying the oxidative stress caused by CDT. Meanwhile, ROS enhances the cytotoxicity of chemotherapy drugs by inhibiting antioxidant defense mechanisms, such as the Nrf2 pathway. This combined therapeutic strategy not only overcomes CDT's dependence on H₂O₂ production but also addresses the limited efficacy of chemotherapy drugs in drug-resistant tumors. By enhancing oxidative stress intensity across multiple dimensions, it achieves precise treatment through multiple targets and mechanisms. This research finding holds significant implications for tumor therapy.

The chemotherapeutic drug doxorubicin (DOX), an anthracycline antibiotic, has benefited a large number of cancer patients over the past several decades^[54]. DOX not only causes DNA damage in cells, but under aerobic conditions, it can also upregulate the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in cells, further catalyzing the reaction between NADPH oxidase and O₂ to generate superoxide radicals (O₂ ^•-). O₂ ^•-can induce oxidative damage to cells, leading to cell death. Additionally, under the action of superoxide dismutase, O₂ ^•-can produce large amounts of H₂O₂, thereby promoting CDT therapy^[55]. However, the hypoxic tumor microenvironment (TME) limits the effectiveness of chemotherapy. To enhance the efficiency of combined CDT and chemotherapy treatment, Gao et al.^[56] adopted a bottom-up approach to construct the nanocatalytic drug CaO₂ @DOX@ZIF-67. This nanodrug rapidly disintegrates in the acidic TME, with CaO₂reacting with water to generate O₂and H₂O₂, while ZIF-67 releases Co²⁺. Co²⁺can undergo a Fenton-like reaction with H₂O₂to produce •OH. The generation of O₂relieves tumor cell hypoxia, allowing DOX to exert its effects more effectively. This nanodrug provides a new strategy for combined CDT/chemotherapy treatment (Figure 5). Cai et al.^[57] reported a strategy based on cobalt single-atom nanoenzymes that trigger cascade enzymatic reactions in the TME, specifically by loading Co single-atom catalysts (Co-SAs@NC) onto nitrogen-doped porous carbon for tumor-specific therapy. Co-SAs@NC not only mimics catalase activity to catalyze the production of O₂from endogenous H₂O₂within cells, but also simulates oxidase activity to continuously catalyze the conversion of O₂into highly toxic O₂ ^•-. In vivo experiments demonstrated that, thanks to efficient O₂ ^•-generation and synergistic effects with DOX, nano-catalytic therapy based on Co single-atom materials significantly enhanced the anti-tumor efficacy of combined CDT/chemotherapy while avoiding significant damage to normal tissues. Carrier-free nanoprobes have advantages such as high drug-loading capacity, simple preparation methods, and environmental friendliness, attracting widespread attention from researchers in recent years. Based on this, Zhao et al.^[58] formed a carrier-free nanoprobe drug by self-assembling carbon dots, copper ions, and DOX. In the acidic TME, the nanodrug rapidly dissociates, releasing Cu²⁺, carbon dots, and DOX. Cu²⁺consumes GSH and generates •OH through a Fenton-like reaction. Combined with the peroxidase-like activity of carbon dots and the effects of DOX, the nanodrug achieves enhanced combined chemotherapy/CDT treatment. This approach provides a new strategy for designing and synthesizing carrier-free nanoprobes for synergistic tumor therapy. Wang et al.^[59] constructed a multifunctional nanoparticle integrating dual targeting of tumor tissue, cells, and mitochondria, tumor-specific drug release, and endogenous ROS generation, enabling MRI-guided combined chemotherapy/CDT treatment of tumors. The nanoparticle not only actively targets tumor tissue and accumulates in tumor cells, but also responds to the acidic TME by releasing chemotherapy drugs such as DOX and camptothecin, as well as CDT drugs. Subsequently, due to mitochondrial targeting, the CDT drugs accumulate in the mitochondria of tumor cells and generate large amounts of reactive oxygen species. The burst of endogenous reactive oxygen species and the release of chemotherapy drugs achieve synergistic effects between chemotherapy and CDT, ultimately resulting in more pronounced cell death compared to single therapies. In vivo experiments in mice showed that the nanoparticles were nearly harmless but exhibited strong cytotoxicity against tumors.

Cisplatin is a classic chemotherapy drug that can cross-link with DNA in tumor cells, disrupting DNA replication and transcription processes, thereby leading to tumor cell death^[60]. However, cisplatin readily reacts with GSH, and the weakly acidic and hypoxic tumor microenvironment (TME) also negatively affects the efficacy of cisplatin-mediated chemotherapy. To enhance the therapeutic effect of cisplatin, He et al.^[61] developed a copper/cisplatin hybrid silica nanomedicine (CuO₂/DDP@SiO₂), which was used for synergistic chemotherapy/CDT-based cancer treatment. After entering tumor cells, CuO₂ reacts with water to generate O₂, alleviating the hypoxic condition of the TME. Additionally, Cu²⁺ can react with GSH, depleting it. These conditions enable cisplatin to function more effectively, thereby promoting tumor treatment. This work provides a novel perspective on the synergistic effects of CuO₂ and cisplatin.

The combination of chemotherapy and CDT addresses the limitations of chemotherapy drugs used alone and also enhances the efficacy of CDT. However, the high toxicity and drug resistance of chemotherapy drugs remain serious challenges in cancer treatment. In future research, self-assembled nanoplatforms will be a promising option for combined chemotherapy/CDT therapy.

Similar to PTT, PDT is also a non-invasive light-mediated therapy. It activates photosensitizers by absorbing light energy at specific wavelengths, which in turn excites O₂to generate ROS that are toxic to cells, thereby damaging tumor cells^[62]. However, the limited penetration depth of the excitation light and the inherent hypoxic microenvironment of solid tumors restrict the therapeutic efficacy of PDT. Combining CDT with PDT can significantly enhance the anti-tumor effect through multiple mechanisms. PDT generates H₂O₂and singlet oxygen (¹O₂) under light activation via photosensitizers^[63], providing catalytic substrates for CDT and enhancing the Fenton-like reaction to produce ·OH. Meanwhile, CDT alleviates PDT's dependence on O₂by releasing O₂, and strengthens the anti-tumor immune response. This combined therapy overcomes the limitations of single therapies in terms of oxygen dependency, insufficient H₂O₂supply, and inadequate deep-tissue killing ability, significantly improving treatment efficiency and precision, and demonstrating great application potential in tumor therapy. Therefore, combining PDT with CDT will help improve the therapeutic outcomes for tumors.

To increase the concentration of O₂in the TME and enhance the efficacy of combined PDT and CDT, some researchers have employed MOFs in conjunction with metal compounds such as CaO₂and MnO₂, which react with endogenous substances in tumor cells to generate O₂ ^[64]. For example, Shen et al.^[65]encapsulated CaO₂nanoparticles, Fenton reagent Fe²⁺, and the photosensitizer chlorin e6 (Ce6) within ZIF-90, followed by further surface modification with PEG, to synthesize a pH-responsive, degradable CaO₂@ZIF-Fe/Ce6@PEG nanoplatform. In the weakly acidic TME, ZIF-90 degrades, releasing CaO₂nanoparticles, Fe²⁺, and Ce6. The CaO₂participates in reactions to produce O₂and H₂O₂, alleviating the hypoxic condition of the TME. The generation of Ca²⁺leads to calcium overload in tumor cells, amplifying cellular oxidative stress and causing mitochondrial dysfunction. The Fenton reagent Fe²⁺reacts to produce •OH, while the photosensitizer Ce6, upon specific light irradiation, excites O₂to generate ¹O₂. These substances act synergistically to enhance the efficacy of PDT/CDT (Figure 6). Li et al.^[66]coated the surface of the porphyrin-based MOF material PCN-224 with an MnO₂nanoshell, yielding PCN@MnO₂, and loaded DOX into it, then modified it with hyaluronic acid (HA) to obtain the intelligent PCN@MnO₂@DOX@HA nanoplatform. This platform simultaneously achieves TME-triggered controlled drug release, self-supply of O₂, and MRI imaging, thereby enhancing tumor-specific PDT/CDT therapy. In the TME, MnO₂reacts with endogenous H₂O₂to generate O₂, and it can also react with GSH to produce Mn²⁺for enhanced T₁contrast agent MRI imaging. As the fluorescence of PCN-224 recovers and the chemotherapeutic drug DOX is released, the efficacy of CDT is enhanced, promoting tumor cell death. This TME-triggered combined PDT/CDT therapy holds promise for achieving highly targeted treatment of hypoxic tumors while minimizing side effects.

Traditional photosensitizers can be activated under visible light irradiation at 400–700 nm and have been successfully applied in the treatment of superficial tumors such as skin cancer and esophageal cancer. However, for deeper-seated tumors, lasers with specific wavelengths are required to induce therapeutic effects. Compared to NIR-I light and ultraviolet-visible light, the NIR-II window offers greater tissue penetration depth and lower autofluorescence^[67]. Therefore, NIR-II light has become a more ideal light source for PDT, particularly suitable for the treatment of deep-seated tumors. In recent years, the combined use of NIR-II light-guided PDT and CDT for tumor treatment has attracted widespread attention in academic circles. For example, Wang et al.^[68]first synthesized Ag₃SbS₃via a hydrothermal method, then modified it with PEG and loaded MnO₂, ultimately constructing a multifunctional MnO₂/Ag₃SbS₃nanoparticle. After intravenous injection, the nanomedicine can accumulate in tumor tissues through the enhanced permeability and retention effect. Once internalized by tumor cells, the TME promotes the degradation of MnO₂/Ag₃SbS₃into Mn²⁺and ultra-small Ag₃SbS₃nanoparticles, which can be rapidly excreted through the liver and kidneys, thus avoiding nonspecific accumulation in normal tissues. The released Mn²⁺can catalyze the generation of •OH from H₂O₂via a Fenton-like reaction, while Ag₃SbS₃serves as a NIR-II-guided PTT/PDT nanotherapeutic agent for tumor imaging and treatment. Additionally, MnO₂/Ag₃SbS₃can continuously consume GSH and produce oxygen, enhancing the therapeutic efficacy of CDT and PDT. Notably, MnO₂/Ag₃SbS₃achieves a single-laser-triggered NIR-II PTT/PDT synergistic effect under 1064 nm laser irradiation, demonstrating excellent tumor treatment outcomes and even the potential for complete tumor eradication. Furthermore, MnO₂/Ag₃SbS₃can also be used for photoacoustic and magnetic resonance dual-modal imaging, enabling more accurate treatment guidance. Therefore, MnO₂/Ag₃SbS₃provides a solid foundation for dual-modal MRI/photoacoustic (PA) imaging-guided precision tumor therapy and an excellent integrated environment-sensitive nanoplatform for oxygen self-supplied CDT/PDT synergistic treatment under 1064 nm laser irradiation (Figure 7). Li et al.^[69]designed and prepared LDNPs@Fe/Mn-ZIF-8, a NIR-responsive and NIR-II imaging-guided PDT and CDT synergistic catalytic nanoplatform. By optimizing the active shell doped with Yb³⁺/Ce³⁺, the Fe/Mn-ZIF-8 photosensitizer can provide stable excitation energy for photocatalysis-driven PDT. Moreover, the TME-responsive degradation of Fe/Mn-ZIF-8 further enhances CDT.

The combined treatment of PDT and CDT addresses the limitations of single-modality therapy, offering a new option for the clinical treatment of deep-seated tumors. However, the hypoxic tumor microenvironment (TME) and limited light penetration depth hinder its clinical application. Therefore, developing CDT/PDT agents that can autonomously generate O₂, absorb in the near-infrared region, and achieve precise targeted therapy will be an important research direction in the future.

The combined application of CDT with PTT, chemotherapy, and PDT significantly enhanced therapeutic efficacy and effectively reduced side effects. Additionally, combining CDT with other cancer treatment modalities (such as starvation therapy, immunotherapy, radiotherapy, and synergistic treatments involving multiple approaches) also demonstrates promising application prospects.

Glucose, oxygen, and other nutrients are indispensable for tumor growth. Cutting off the supply of these nutrients can effectively inhibit the continuous proliferation of tumors; this therapeutic approach is known as starvation therapy^[70]. By using GOx to consume glucose and generate H₂O₂ and gluconic acid, not only is tumor growth inhibited, but also raw materials are provided for the Fenton reaction within tumor cells, enhancing its reaction rate. Therefore, studies have shown that designing a starvation therapy triggered by CDT combined with GOx can improve anti-tumor efficacy^[71]. For example, Guo et al.^[72]prepared a human serum albumin (HSA)-GOx mixture loaded with tirapazamine (TPZ), which was then modified with a metal-polyphenol network composed of Fe³⁺ and polyphenols, resulting in a nanocomposite (HSA-GOx-TPZ-Fe³⁺-TA). In this system, polyphenols accelerate the therapeutic rate of chemodynamic therapy, while GOx achieves starvation therapy by consuming glucose and provides a hypoxic environment for TPZ-mediated chemotherapy. This study thus realizes a synergistic treatment combining starvation therapy, chemotherapy, and CDT. Additionally, Liang et al.^[73]designed and constructed a nanoplatform consisting of copper-doped mesoporous Prussian blue encapsulating GOx and hyaluronic acid-modified nitric oxide donors (GOx@CMPB-HN). This nanoplatform targets tumor cells via nitric oxide donors, while GOx consumes glucose inside tumor cells, producing H₂O₂ and gluconic acid, further enhancing the acidity of the TME and providing a better catalytic environment for Cu²⁺-mediated Fenton-like reactions. Moreover, Cu²⁺ doping significantly improves the photothermal conversion performance of CMPB, and the temperature increase induced by photothermal therapy accelerates the CDT catalytic reaction. This combination of PTT, CDT, and starvation therapy demonstrates remarkable therapeutic effects and offers a new feasible approach for the design of future anti-tumor treatment platforms (Figure 8). Besides using GOx, metal ions can also be utilized to deplete glucose within tumor cells. For instance, Xu et al.^[74]constructed ZnO₂@Au@ZIF-67 nanoparticles. In the acidic TME, the pH-responsive degradation of the shell layer ZIF-67 triggers the release of Co²⁺, a Fenton-like catalyst. Subsequently, the exposed ZnO₂ reacts with H₂O to generate O₂ and H₂O₂. The generated O₂ not only alleviates the hypoxic state in the TME but also interacts with the Au NPs initially coated on ZnO₂, catalyzing intracellular glucose consumption and producing another source of H₂O₂. While glucose depletion leads to tumor cell starvation, the dual-source H₂O₂ reacts with the Co²⁺ catalyst to generate highly toxic •OH radicals for CDT. These nanoparticles thus provide a novel strategy to enhance the therapeutic efficacy of CDT combined with starvation therapy.

Immunotherapy is a method of cancer treatment that modulates the human immune system^[18]. Compared with traditional cancer treatments, immunotherapy exhibits stronger targeting ability and more durable therapeutic effects. However, single-agent immunotherapy may lead to excessive activation of the immune system, triggering immune responses and tissue damage. Additionally, cancer cells can evade immune surveillance through multiple mechanisms, thereby suppressing the efficacy of immunotherapy. Combining CDT with immunotherapy can alter the tumor's immune microenvironment and enhance the anti-tumor effects of immunotherapy. The •OH generated by CDT can induce tumor cell apoptosis and release tumor antigens, promoting the activation of T cells by immunotherapy and helping to overcome tumor immune escape^[75].Yuan et al.^[76] reported a synergistic strategy that enhances the Fenton reaction and alleviates the immunosuppressive tumor microenvironment. First, they used apatinib-loaded micelles to target tumor vessels, promoting vascular normalization and relieving hypoxia in the TME, thereby inducing polarization of M2 macrophages toward the anti-tumor M1 phenotype. This process promotes the secretion of tumor necrosis factor-α and interleukin-6, activates T cells, and enhances the anti-tumor immune response. Subsequently, they employed ascorbic acid-loaded liposomes to enhance the conversion of Fe³⁺ to Fe²⁺; ascorbic acid can also react with O₂ to generate H₂O₂, further increasing the rate of the Fenton reaction. This strategy combines CDT with immunotherapy, effectively enhancing the therapeutic efficacy against tumors.

Radiotherapy is a clinical cancer treatment modality that uses X-rays to induce DNA damage and inhibit tumors^[77]. The efficacy of radiotherapy is primarily influenced by intracellular O₂ concentration and the radiosensitivity of therapeutic agents. With the development of interdisciplinary fields such as chemistry, physics, and materials science, a new type of radiosensitizing material has emerged. Its therapeutic effect is mainly achieved through a series of photoelectric phenomena triggered by high-energy photons or particles interacting with the material, including photoelectric absorption, Compton scattering, and pair production. When these reactions occur in vivo, they generate a large number of high-energy particles such as Auger electrons and photoelectrons, leading to the production of various ROS within tumor cells, significantly increasing oxidative stress inside the tumor and thereby inducing tumor cell death^[78]. Lu et al.^[79]designed an electron-supplementing strategy to accelerate the conversion of Fe³⁺ to Fe²⁺. They selected Hensify (chemical composition: HfO₂) as a radiosensitizer. To ensure efficient electron transfer from HfO₂ to Fe₃O₄, they utilized dopamine-polyethylene glycol-amine (DA-PEG-NH₂) and polyacrylic acid (PAA) to achieve phase transfer of Fe₃O₄ NPs via amide conjugation, followed by conjugation with HfO₂, forming Fe₃O₄ @HfO₂ composite NPs (FH). Subsequently, they further coated the surface of FH with the cell membrane of bone marrow stromal cells (MS-5 cells), creating a cell-membrane-cloaked composite nanoparticle (abbreviated as FHCM). After these nanoparticles target and enter tumor cells, under irradiation with 4 Gy X-rays, HfO₂ generates a large number of photoelectrons to charge Fe₃O₄, thereby accelerating the Fenton reaction. Additionally, FHCM produces a significant amount of ROS, causing damage to tumor cells. The superparamagnetic properties of Fe₃O₄ and the high X-ray attenuation capability of hafnium enable these nanoparticles to perform dual-modal CT-MRI imaging. This combination of RT and CDT holds great potential for image-guided tumor therapy (Figure 9).

Currently, combined treatments of CDT with other therapies have achieved more significant antitumor effects than CDT used alone. Encouragingly, multimodal therapies that integrate three or more treatment modalities into a single nanomaterial may yield even better results than dual-modal approaches^[80]. Wang et al.^[81]encapsulated K7M2 osteosarcoma cells around mesoporous Fe₃O₄nanoparticles loaded with perfluoropentane and glucose oxidase, thereby fabricating the nanoplatform M-mFeP@O₂-G. Surface-modified K7M2 osteosarcoma cells enable the nanoparticles to specifically target tumor cells. As an inducer of the Fenton reaction, Fe₃O₄exhibits excellent photothermal performance, accelerating the generation of •OH. GOx catalyzes the conversion of glucose into H₂O₂, placing tumor cells in a state of starvation, while perfluoropentane provides O₂for this cascade reaction, further enhancing the Fenton process. This integrated combination therapy of CDT/PTT/starvation therapy offers a new strategy for designing highly effective tumor treatment platforms. Xiong et al.^[82]combined an axial Pt(Ⅳ) prodrug (A-Pt) containing two artemisinin succinate molecules with the NIR-Ⅱ photothermal agent IR1048, and encapsulated A-Pt and IR1048 with human serum albumin to prepare a nanomedicine (A-Pt-IR NP) for efficient delivery in 4T1 tumor-bearing mice. After intravenous injection, mild hyperthermia generated by IR1048 under NIR-Ⅱ irradiation raises the local tumor temperature to 43°C, accelerating the rate of the Fenton reaction. A-Pt is reduced by GSH into cisplatin and artemisinin; cisplatin disrupts tumor cell DNA, while artemisinin reacts with endogenous Fe²⁺to perform CDT, generating ROS and inducing tumor cell death. NIR-Ⅱ-mediated CT/CDT opens up new avenues for the clinical application of CDT (Figure 10). Wang et al.^[83]employed the PDA-Hemin-DOX-FA (PHDF) nanomedicine for combined tumor treatment. This nanomedicine targets tumor cells via folate, and under the weakly acidic conditions of the TME, the nanoparticles dissociate. Hemin not only reacts with intracellular H₂O₂to produce large amounts of •OH for CDT but also generates oxygen, alleviating the hypoxic state of tumor cells. Under NIR irradiation, this nanomedicine not only demonstrates excellent PTT therapeutic effects but also promotes DOX uptake and •OH generation, thereby enhancing the efficacy of CT and CDT.

Compared to single-agent therapy, combination therapy involving two or more modalities significantly improves treatment outcomes. However, combination therapy is not merely a simple summation of several drugs; rather, it leverages mutual promotion and synergistic effects to fully exploit the advantages of each agent, thereby maximizing the efficacy of cancer treatment and ultimately achieving an "1+1>2" effect.