Lutetium texaphyrin: A photocatalyst that triggers pyroptosis via biomolecular photoredox catalysis.

Abstract

Photon-controlled pyroptosis activation (PhotoPyro) is a promising technique for cancer immunotherapy due to its noninvasive nature, precise control, and ease of operation. Here, we report that biomolecular photoredox catalysis in cells might be an important mechanism underlying PhotoPyro. Our findings reveal that the photocatalyst lutetium texaphyrin (<b>MLu</b>) facilitates rapid and direct photoredox oxidation of nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, and various amino acids, thereby triggering pyroptosis through the caspase 3/GSDME pathway. This mechanism is distinct from the well-established role of <b>MLu</b> as a photodynamic therapy sensitizer in cells. Two analogs of <b>MLu</b>, bearing different coordinated central metal cations, were also explored as controls. The first control, gadolinium texaphyrin (<b>MGd</b>), is a weak photocatalyst but generates reactive oxygen species (ROS) efficiently. The second control, manganese texaphyrin (<b>MMn</b>), is ineffective as both a photocatalyst and a ROS generator. Neither <b>MGd</b> nor <b>MMn</b> was found to trigger pyroptosis under the conditions where <b>MLu</b> was active. Even in the presence of a ROS scavenger, treating MDA-MB-231 cells with <b>MLu</b> at concentrations as low as 50 nM still allows for pyroptosis photo-activation. The present findings highlight how biomolecular photoredox catalysis could contribute to pyroptosis activation by mechanisms largely independent of ROS.