Cascade Amplification of Photoimmunotherapy via Mitochondrial Dual‐Ion Interference in a Bimetallic‐Organic Framework

ABSTRACT Mitochondria‐targeted photodynamic immunotherapy has emerged as a promising strategy that combines organelle‐specific delivery with immunomodulation for cancer treatment. However, inadequate photosensitizer efficiency and insufficient targeting often limit its therapeutic efficacy. To systematically address these limitations, we developed a ZIF‐90‐based immunomodulatory prodrug exhibiting mitochondria‐associated accumulation that enables tumor therapy by synergistically integrating metal ion interference with in situ photoimmunotherapy. This prodrug undergoes disassembly in the high‐ATP tumor microenvironment, releasing metal ions (Zn 2+ , Mn 2+ ), and 5‐aminolevulinic acid (5‐ALA). 5‐ALA is metabolized via the heme biosynthesis pathway to generate photoactive protoporphyrin IX (PpIX) within mitochondria. A detailed molecular docking and mechanistic study reveals that Zn 2 + potently inhibits ferrochelatase (FECH) by displacing its native Fe 2 + cofactor, thereby blocking PpIX‐to‐heme conversion and enabling unprecedented photosensitizer retention at the target site. The co‐released Zn 2+ /Mn 2+ ions further disrupt mitochondrial complexes I/II, resulted in electron transport chain collapse and amplified oxidative stress. Concurrently, Mn 2 + release was associated with cGAS‐STING‐related immune signaling and enhanced antitumor immune responses. This work demonstrates mitochondrial ion interference as a therapeutic cascade to enhance photoimmunotherapy, overcoming the limitations of traditional photodynamic therapy and immunosuppressive tumor microenvironments.