An O₂-Independent Copper(II) Phototherapeutic Agent for Photoactivating H₂O₂ to Enhance Antitumor Immunotherapy

The characteristics of tumor cells and their microenvironment, including high rates of recurrence and metastasis, insufficient oxygen (O₂) supply, and the immunosuppressive microenvironment, severely limit the effectiveness of conventional photodynamic therapy for hypoxic tumors. Herein, we report an O₂-independent nano-photocatalyst (NanoPcCu), rationally designed to provide near-infrared light induced self-adaptive photodynamic processes, enhancing the generation of type I reactive oxygen species (OH· and O₂^•-) and thermal effects to promote photoimmunotherapeutic antitumor responses. Simple copper (Cu)(II) and amino modifications on phthalocyanine (Pc) endowed (i) the self-assembled metal-Pc complex (NanoPcCu) with remarkable photothermal and photoacoustic effects and (ii) photoredox performance to catalytically convert H₂O₂ to highly toxic ·OH upon photooxidation between Cu(II) and Cu(I) under normoxic and hypoxic conditions. These features allowed NanoPcCu to achieve a prominent phototherapeutic response under normoxic and hypoxic conditions. Notably, NanoPcCu-mediated phototherapy not only suppresses tumor growth completely in a preclinical model but also activates antitumor immune responses through the synergistic effects of photoredox activity and photothermal therapy. This study provides a reliable method to develop transition metal Pc complexes as efficient phototheranostic agents to overcome the hypoxic and immunosuppressive microenvironment of solid tumors.