Current progress in the regulation of endogenous molecules for enhanced chemodynamic therapy

Chemodynamic therapy (CDT) is a potential cancer treatment strategy, which relies on Fenton chemistry to transform hydrogen peroxide (H₂O₂) into highly cytotoxic reactive oxygen species (ROS) for tumor growth suppression. Although overproduced H₂O₂ in cancerous tissues makes CDT a feasible and specific tumor therapeutic modality, the treatment outcomes of traditional chemodynamic agents still fall short of expectations. Reprogramming cellular metabolism is one of the hallmarks of tumors, which not only supports unrestricted proliferative demands in cancer cells, but also mediates the resistance of tumor cells against many antitumor modalities. Recent discoveries have revealed that various cellular metabolites including H₂O₂, iron, lactate, glutathione, and lipids have distinct effects on CDT efficiency. In this perspective, we intend to provide a comprehensive summary of how different endogenous molecules impact Fenton chemistry for a deep understanding of mechanisms underlying endogenous regulation-enhanced CDT. Moreover, we point out the current challenges and offer our outlook on the future research directions in this field. We anticipate that exploring CDT through manipulating metabolism will yield significant advancements in tumor treatment.