Mitochondria targeting photoredox catalyst-induced pyroptosis for enhanced immunotherapy against hypoxic tumor cells

Hypoxia and immunosuppression microenvironment have been considered as two obstacles of traditional cancer therapies. To tackle these problems, we constructed a mitochondria-targeting photocatalyst NBPy, which can effectively eradicate hypoxic tumor cells and cause immunogenic cell death (ICD) via caspase-3/Gasdermin E (GSDME) mediated pyroptosis. NBPy could generate reactive oxygen species (ROS) via the type I PDT process and photocatalyze nicotinamide adenine dinucleotide (NADH) to NAD+, leading to mitochondrial electron transport chain (ETC) blockade and severe mitochondrial dysfunction. Moreover, NBPy evokes a more intensive effect of pyroptosis and ICD than its lysosome targeting counterpart (NBH) with much less dark toxicity. The photon-triggered pyroptosis significantly alleviated the immunosuppressive tumor microenvironment (TME), and promoted the maturation of dendritic cells and the intratumoral infiltration of T lymphocytes, which activated the systemic immunity for effective suppression of distant tumors. This study provides an excellent strategy for outstanding cancer immunotherapy against hypoxic tumor cells.