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

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. (C) 2020 Published by Elsevier Ltd.

Automated summary

The study introduces a new oxygen-independent photosensitizer to overcome limitations in tumor treatment due to hypoxia, self-quenching of photosensitizers, and immune suppression. The new photosensitizer effectively activates immune responses and shows promise for cancer therapy.