Nanozyme-Driven Tumor Microenvironment Remodeling for Potentiated Phototherapy–Immunotherapy

Abstract Tumor hypoxia critically drives the development of an immunosuppressive tumor microenvironment (TME) and accelerates tumor progression. Besides, hypoxia seriously restricts O2-dependent reactive oxygen species (ROS) generation, thereby severely compromising the therapeutic efficacy of photodynamic therapy (PDT). To address these challenges, we developed a multifunctional manganese (Mn)-based nanozyme (MLDHI) loaded with indocyanine green (ICG) to reprogram the immunosuppressive TME for potentiated phototherapy combined with immunotherapy. Upon intratumoral injection, the Mn4+ doped within the nanozyme shell catalyzes the decomposition and conversion of overexpressed H2O2 in the tumor tissue into O2, markedly alleviating hypoxia and supplying O2 for ICG-mediated PDT to enhance cytotoxic ROS production. The resulting phototherapeutic efficacy promotes immunogenic cell death (ICD) of tumor cells and releases double-stranded deoxyribonucleic acid (dsDNA), which together with Mn2+ embedded in the lamellar structure synergistically activates the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway, triggering interferon (IFN)-β release and dendritic cell (DC) maturation. In a breast tumor model, a single intratumoral injection of MLDHI plus laser irradiation achieved 75% tumor ablation and elicited robust immune memory to prevent recurrence and metastasis.