A Highly Charged Positive Cage Causes Simultaneous Enhancement of Type-II and O2-Independent-Type-I Photodynamic Therapy via One-/Two-Photon Stimulation and Tumor Immunotherapy via PANoptosis and Ferroptosis

To solve the oxygen dependence problem of photodynamic therapy (PDT), it is critical to explore photosensitizers that do not rely on O₂ molecule to generate reactive oxygen species (ROS). Herein, a stable cationic metal-organic cage [Pd₆(RuL^oz₃)₈](BF₄)₂₈ (MOC-88) that possesses high +28 charges is designed. The cage-confined positive microenvironment enables efficient generation of hydroxyl radicals and improved yield of the singlet oxygen under one-/two-photon excitation, showing excellent performance to concurrently enhance Type-II and O₂-independent-Type-I PDT. Moreover, the effective ROS production and robust lipid peroxidation trigger a series of signaling pathways (inflammasome, cyclic guanosine monophosphate–adenosine monophosphate synthase stimulator of interferon genes, and NF-κB) to evoke PANoptosis and ferroptosis in tumor cells, enabling MOC-88 to simultaneously cause the loss of cell membrane integrity, release a series of inflammatory cytokines and damage-associated molecular patterns, stimulate the maturation and antigen presentation ability of dendritic cells, and ultimately activate T-cell-dependent adaptive immunity in vivo to inhibit tumor growth.