Oxygen-independent free radical generation mediated by core-shell magnetic nanocomposites synergizes with immune checkpoint blockade for effective primary and metastatic tumor treatment

Abstract Advanced or metastatic tumor treatment is a long-lasting problem that leads to high mortality. Photodynamic therapy (PDT) has emerged as a promising clinical therapeutic strategy with the ability of destroying local tumors and initiating systemic anti-tumor immune responses for metastasis inhibition. However, the efficacy is typically limited by tumor hypoxia, aggregation caused self-quenching of classic photosensitizers (PSs), and intrinsic or adaptive immune resistance that mediated by cellular and molecular immunosuppressive components. Here, we designed an oxygen-independent photosensitizer by core-shell magnetic nanocomposites (MNCs), with functionalized iron oxide nanoclusters as the core and coordination polymerization of Zinc Tetra (N-methyl-4-pyridyl) porphyrin (ZnTMPyP) as the shell. MNCs PDT induced persistent free radical generation via facilitating an effective electron-hole separation, polarized macrophages to pro-inflammatory M1 phenotype, and activated systemic antitumor immunity. Nevertheless, adaptive immune resistance occurred simultaneously, characterized by highly increased PD-L1 expression on tumor cells, dendritic cells (DCs) and macrophages. As a result, combined use of MNCs PDT with checkpoint blockade effectively suppressed well-established primary tumors as well as tumor metastasis via a ‘trident’ modality, including persistent free radical generation in both normoxic and hypoxic conditions for direct tumor destruction, enhanced frequency of tumor infiltrating-lymphocytes (TILs) and modified tumor immunosuppressive microenvironment with reduced immunosuppressive cells and PD-L1 blockade. We also explore the underlying mechanisms of metastasis inhibition according to the transcriptome expression profiling of lung tissues, which revealed that the ‘trident’ modality altered numerous genes mainly related to immuno-activation and cancer associated signaling pathways. We expect the expanded use of this platform for various types of cancer malignancy.