Invoking ferroptosis and photon-controlled pyroptosis via an integrated therapeutic system for triple-pathway tumor therapy.

Antitumor agents that rely solely on apoptosis often fail to disrupt the complementary cell survival cascades. In this study, we developed a redox-responsive integrated therapeutic system (QSH) that exploited ferroptosis and pyroptosis to enhance tumor therapy. QSH consisted of a dihydroorotate dehydrogenase (DHODH in mitochondria) inhibitor (Q, a ferroptosis inducer) and a photosensitiser (IHcy, a pyroptosis trigger) linked by a disulphide bond. Upon entering cancer cells, QSH could effectively target mitochondria by leveraging the mitochondrial membrane potential. Within the highly redox-stressed tumor microenvironment, the disulfide bonds were cleaved by glutathione (GSH), leading to the release of Q and IHcy, which promoted glutathione peroxidase 4 (GPX4)-mediated ferroptosis (the first pathway). The released Q inhibited DHODH activity within mitochondria, thereby disrupting the DHODH-mediated mitochondrial antioxidant system and also promoting ferroptosis (the second pathway). Under light irradiation, the photodynamic effect of IHcy triggered gasdermin D (GSDMD)-mediated pyroptosis (the third pathway), thereby promoting the release of damage-associated molecular patterns. Significantly, QSH completely suppressed tumor growth in 4T1 breast cancer models due to the synchronous activation of ferroptosis and pyroptosis in tumors. This redox-triggered triple-pathway strategy effectively elevated the level of lipid peroxidation within cells, induced immunogenic cell death, and enhanced tumor sensitivity to treatments.