Tyrosinase Driven‐Intracellular Polymerization of a Porphyrin Derivative Induced Immunogenic Death of Melanoma Cells and Strengthened Photodynamic Therapy

ABSTRACT Therapeutic agents usually must reach diseased tissue and then exert biological effects. While numerous targeted and stimuli‐responsive delivery systems have been developed, their therapeutic outcomes have been limited due to the lack of “precision”. In this study, we present a strategy for in situ polymerization of a porphyrin derivative within melanoma cells triggered by tyrosinase, and subsequent self‐assembly of the polymers into microstructures limiting porphyrin efflux, to achieve “precision medicine” for melanoma. The specific intracellular polymerization and subsequent self‐assembly process induced immunogenic cell death of melanoma cells and transformed immunosuppressive “cold” tumors into immunoactive “hot” tumors by polarizing macrophage into M1 type, stimulating dendritic cell maturation, and improving CD8 T cell infiltration and activation. Furthermore, the intracellularly retained polymeric porphyrin microstructures enhanced photodynamic therapy to synergistically drive improved treatment outcomes. This in situ intracellular polymerization and self‐assembly approach provides a precise and safe alternative to conventional drug‐based cancer therapies.