2024 | Yunjie Xu, Calvin V. Chau, Jieun Lee, Adam C. Sedgwick, Le Yu, Mingle Li, Xiaojun Peng, Jong Seung Kim, Jonathan L. Sessler
Lutetium texaphyrin (MLu) is a near-infrared (NIR) photocatalyst that triggers pyroptosis in cancer cells through biomolecular photoredox catalysis. This study demonstrates that MLu, when exposed to 730 nm light, catalyzes the oxidation of NADH, NADPH, and amino acids, leading to the activation of the caspase 3/GSDME pathway and subsequent pyroptosis. Unlike its role as a photodynamic therapy sensitizer, MLu's mechanism here is distinct, involving photoredox catalysis rather than ROS generation. Two analogs, gadolinium texaphyrin (MGd) and manganese texaphyrin (MMn), were tested as controls; neither triggered pyroptosis under the same conditions. Even with a ROS scavenger, MLu at 50 nM still induced pyroptosis, indicating that the mechanism is independent of ROS. MLu showed significant anticancer activity in breast cancer cell lines, with a low IC50 value and high phototoxicity index. In 3D multicellular spheroids, MLu induced structural collapse and cell death, suggesting its potential as a trigger for photoinduced cancer immunotherapy. The findings highlight the role of biomolecular photoredox catalysis in pyroptosis activation, offering new avenues for cancer treatment.Lutetium texaphyrin (MLu) is a near-infrared (NIR) photocatalyst that triggers pyroptosis in cancer cells through biomolecular photoredox catalysis. This study demonstrates that MLu, when exposed to 730 nm light, catalyzes the oxidation of NADH, NADPH, and amino acids, leading to the activation of the caspase 3/GSDME pathway and subsequent pyroptosis. Unlike its role as a photodynamic therapy sensitizer, MLu's mechanism here is distinct, involving photoredox catalysis rather than ROS generation. Two analogs, gadolinium texaphyrin (MGd) and manganese texaphyrin (MMn), were tested as controls; neither triggered pyroptosis under the same conditions. Even with a ROS scavenger, MLu at 50 nM still induced pyroptosis, indicating that the mechanism is independent of ROS. MLu showed significant anticancer activity in breast cancer cell lines, with a low IC50 value and high phototoxicity index. In 3D multicellular spheroids, MLu induced structural collapse and cell death, suggesting its potential as a trigger for photoinduced cancer immunotherapy. The findings highlight the role of biomolecular photoredox catalysis in pyroptosis activation, offering new avenues for cancer treatment.