Currently, malignant tumor has become a major threat to human health, considerable attention has been paid to explore more effective therapeutic strategies for cancer treatment (Cao M. et al., 2020; Ferlay et al., 2021; Sung et al., 2021). With the development of nanoscience and nanobiotechnology, significant progress has been achieved in cancer therapy in the last decades (Wicki et al., 2015; Lin et al., 2022). However, effective treatment for cancer still presents significant challenges, for example, multidrug resistance is one of the difficult issues in current clinical chemotherapy treatment. Therefore, it is particularly necessary to develop new therapeutic agents and approaches for the more satisfactory cancer treatment (Rasool et al., 2022). In recent years, chemodynamic therapy (CDT) has attracted extensive attention in the field of tumor therapy.

CDT is inherently oxidative stress-induced cell killing process, it was first proposed in 2016 (Zhang et al., 2016). Briefly, by using the transition metal ions (Fe²⁺, Cu⁺, Mn²⁺, and so on), intracellular hydrogen peroxide (H₂O₂) is catalyzed to generate high reactivity hydroxyl radical (•OH), which would induce oxidative stress and further the death of cancer cells (Zhang X. et al., 2020; Chen et al., 2020; Zhang H. et al., 2021) (Figure 1). Generally, in order to improve the specificity and therapeutic efficacy of CDT, those CDT agents are usually designed as nanosystems. In this review, recent advancements of nanosystems for enhancing the CDT application and efficiency are reviewed. The major obstacles for the clinical applications of CDT are introduced, and those CDT enhanced strategies that CDT in combination with other therapies are focused and emphasized, such as combined with photothermal therapy, immunotherapy, sonodynamic therapy, and so on. The present review aims to provide better understanding of how to design effective chemodynamic agents, thus to broaden the application of CDT and maximize the CDT therapeutic effectiveness.

It is well known that the tumor microenvironment (TME) exhibits unique physiological features compare with the normal tissues, including acidic pH, hypoxia, overproduced H₂O₂, the alteration of specific enzyme activities and elevated level of glutathione (GSH) (Roma-Rodrigues et al., 2019; Zhang Y. et al., 2022). On one side, these features of TME play crucial roles in tumor initiation, progression, metastasis, and even resistance to therapy. On the other side, the unique physiological conditions of TME can also be used as the stimuli to trigger the antitumor drug release at tumor sites to improve antitumor efficacy, which are known as the TME stimuli-responsive drug delivery systems (Wu and Dai, 2017; Li et al., 2021).

Considering the acidic and H₂O₂ overexpressed conditions in TME, the concept of CDT was proposed as a therapeutic strategy that using Fenton or Fenton-like reaction to generate hydroxyl radical in tumor site. In the first report of CDT, ferrous ions (Fe²⁺) was released from iron-based nanomaterials, which could catalyze endogenous H₂O₂ decomposition into •OH under acidic conditions of TME (Fe²⁺ + H₂O₂ → Fe³⁺ + •OH + OH⁻, known as Fenton reaction). The over produced •OH, one type of cytotoxic reactive oxygen species (ROS), had strong oxidative activity and caused severe oxidative damage to induce tumor apoptosis by phospholipid peroxidation, mitochondrial dysfunctions, and DNA damage (Khan et al., 2012; Srinivas et al., 2019).

Besides Fenton reaction, Fenton-like reactions are also employed for CDT application. Not restricted to iron, other reactive metal components, such as Cu⁺, Mn²⁺, Mo⁶⁺, are used in Fenton-like reaction to catalyze the generation of •OH from H₂O₂ (Cao et al., 2019, Cao et al., 2020 S.; Liang et al., 2021, 2022; Lin et al., 2021). It should be noted that Fenton reaction highly relies on the overexpression of H₂O₂ and acidic condition of TME, which makes CDT strategy much safer to the normal tissues, since the Fenton reaction was suppressed under the neutral and insufficient H₂O₂ conditions in the healthy cell microenvironment.

As a type of ROS-mediated cancer treatment modality, there is considerable development of understanding and in CDT during the last years. However, there are still challenges and limitations that hinder its further application in clinical. First, the acidic environment of solid tumor site is insufficient to trigger the efficient Fenton/Fenton-like reaction; second, the endogenous H₂O₂ level in tumor cells is not enough to generate adequate •OH to induce apoptosis of tumor cells; third, the high concentration of reduced glutathione and redox homeostasis of tumor cells could eliminate the free radical and weaken the CDT effect.

From the perspective of chemical kinetic, hydroxyl radicals could be catalyzed via Fenton/Fenton-like reaction over a wide range of pH conditions (between acidic and neutral pH) (Zhu et al., 2019). However, the efficiency and reactivity of Fenton reaction strongly depend on the pH condition, the reactivity is obviously increased in the acidic pH range (pH 2–4), and strongly reduced (even lost) in alkaline media. Considered the TME is slightly acidic pH condition (pH 6.5–6.8), at one side, the limited reactivity of Fenton/Fenton-like reaction in healthy tissues (pH 7.2–7.4) could avoid the damage on healthy tissues and cells, which makes CDT might selectively kill tumor cells; on the other side, the weakly acidic TME limits the efficiency of Fenton/Fenton-like reactions, which significantly reduce the generation of •OH.

To address the problem of insufficient acidity, attempts have been made to reconstitute the tumor microenvironment via in situ H⁺ generation strategy. For example, several studies have integrated glucose oxidase (GOx) into CDT agents, since GOx can oxidize glucose to gluconic acid to further increases acidity at TME, thus could enhance Fenton/Fenton-like reaction efficiency (Cheng et al., 2020; Zhang X. et al., 2021). It should be noted that the tumor cells employ various mechanisms to maintain cellular homeostasis during tumorigenesis and metastasis, this property makes the in situ acidization of intracellular strategy couldn’t support a long-term change. Therefore, the design and development of pH-independent CDT nanotherapeutics and/or combinational therapies with CDT are viable approaches to overcome pH limitations of CDT.

Besides the pH condition, Fenton/Fenton-like systems are also H₂O₂ dependent. Compared to normal cells (extremely low H₂O₂ level), the tumor cells produce and accumulate a large amount of H₂O₂ (100 μM–1 mM). However, the initial endogenous H₂O₂ level in tumor cells was still not enough to generate sufficient •OH to achieve satisfactory antitumor therapeutic effect. In addition, there are endogenous reducing substances that are involved in maintaining cellular redox homeostasis in the tumor cells. These reductive substances, for example reduced glutathione, could mitigate oxidative stress and repair the oxidative damage. Therefore, increasing H₂O₂ concentration and reducing GSH level in tumor cells are potential approaches to enhance the efficacy of CDT. To overcome the limited-H₂O₂-level obstacle, tremendous H₂O₂ self-supplying systems are designed to enhance the efficiency of Fenton/Fenton-like reactions to achieve satisfactory CDT effect. From the reported studies, there are two important design roles for constructing these H₂O₂ self-supplying systems: 1) delivery of exogenous H₂O₂ to tumors (Gao et al., 2019; Han et al., 2020; Zhao et al., 2022); 2) promote the ability of endogenous H₂O₂ production (Liu et al., 2020; Sang et al., 2020; Jiang et al., 2022).

With the rapid expansion of chemistry and materials science, nanotechnology shows great potential to overcome the limitations of conventional tumor therapy, and nanosystems (or nanotherapeutics) are regarded as one of the most promising strategies for better tumor treatment (Zhang P. et al., 2022). The recent reports have revealed that the combination therapy strategies with CDT nanosystems can optimize the therapy effects and minimize the toxicity and adverse effects of treatment (He et al., 2021; Yang et al., 2021; Liu Y. et al., 2022; Hao et al., 2022).

Although it has been proven that CDT is an ideal therapeutic approach for tumor therapy, the intrinsic barrier of TME is the main obstacle to hinder the further development and clinical translation of CDT. Fortunately, with the rapid expansion of nanoscience and nanobiotechnology, there are more nanosystems have been designed and studied that have potential to overcome those challenges of CDT. However, there are still some problems need to be solved before further clinical applications:

(1) Biosafety issues. At the cellular level, CDT-based nanosystems can enter cells in a variety of approaches, which may lead to changes or even loss of normal cellular functions, resulting in unnecessary toxic side effects. Especially, the current reported CDT-based nanosystems are mainly inorganic or hybrid nanomaterials, which are liable to elicit in vivo immune response. Thus, the biosafety issue of CDT-based nanosystems has raised intense concerns in the clinical applications.

In the future, research efforts should shift to practical trials of using CDT and CDT-based combined therapy strategies in disease treatment. There is still a long way to go before achieving clinical application, we expect more nanosystems for CDT therapy are designed and more cancer patients will benefit from this treatment.