Nanozyme-Driven Tumor Microenvironment Remodeling for Potentiated Phototherapy–Immunotherapy
TL;DR
A multifunctional manganese-based nanozyme loaded with indocyanine green (ICG) is developed to reprogram the immunosuppressive TME for potentiated phototherapy combined with immunotherapy and elicits robust immune memory to prevent recurrence and metastasis.
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.