Abstract: In recent years, chemodynamic therapy (CDT) has received extensive attention as a novel means of cancer treatment. The CDT agents can exert Fenton and Fenton-like reactions in the acidic tumor microenvironment (TME), converting hydrogen peroxide (H₂O₂) into highly toxic hydroxyl radicals (·OH). However, the pH of TME, as an essential factor in the Fenton reaction, does not catalyze the reaction effectively, hindering its efficiency, which poses a significant challenge for the future clinical application of CDT. Therefore, this paper reviews various strategies to enhance the antitumor properties of nanomaterials by modulating tumor acidity. Ultimately, the performance of CDT can be further improved by inducing strong oxidative stress to produce sufficient ·OH. In this paper, the various acidification pathways and proton pumps with potential acidification functions are mainly discussed, such as catalytic enzymes, exogenous acids, CAIX, MCT, NHE, NBCn1, etc. The problems, opportunities, and challenges of CDT in the cancer field are also discussed, thereby providing new insights for the design of nanomaterials and laying the foundation for their future clinical applications.
Keywords: chemodynamic therapy, Fenton/Fenton-like reactions, tumor microenvironment, reactive oxygen specie