To solve the oxygen dependence problem of photodynamic therapy (PDT), it is critical to explore photosensitizers that do not rely on O 2 molecule to generate reactive oxygen species (ROS). Herein, a stable cationic metal‐organic cage [Pd 6 (RuL oz 3 ) 8 ](BF 4 ) 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 O 2 ‐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.

A Highly Charged Positive Cage Causes Simultaneous Enhancement of Type‐II and O<sub>2</sub>‐Independent‐Type‐I Photodynamic Therapy via One‐/Two‐Photon Stimulation and Tumor Immunotherapy via PANoptosis and Ferroptosis

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