Photodynamic therapy initiated immunotherapy of self-delivery re-educator by inducing immunogenic cell death and macrophage polarization

Immunotherapy is a promising clinical treatment strategy against malignant tumor metastasis, however, it often shows an inadequate efficacy owing to the immunosuppressive tumor microenvironment (ITM). Herein, we develop a self-delivery re-educator to induce immunogenic cell death (ICD) and macrophage polarization for photodynamic therapy (PDT) and immunotherapy against breast cancer. To be specific, the self-delivery re-educator (designated as PyroR) is prepared by the self-assembly of the photosensitizer pyropheophorbide-a (Pyro) and TLR agonist resiquimod (R848). Without any carriers, nanosized PyroR exhibits high drug contents and could avoid the side effects raised by excipients. After intravenous administration, PyroR could generate a lot of reactive oxygen species (ROS) for PDT against primary tumor in the presence of light irradiation. Meanwhile, PDT triggered ICD cascade would promote dendritic cells (DCs) maturation and activate cytotoxic T lymphocytes (CTLs) for immunotherapy against distant and metastatic tumors. More importantly, R848 is able to polarize macrophages from M2 to M1 phenotype, which would improve the ITM to enhance antitumor immunity. Consequently, the PDT-initiated immunotherapy of PyroR demonstrates significant inhibition effects on primary, distant and metastatic tumors while causes a minimal system toxicity. This self-delivery re-educating strategy would shed light on constructing carrier-free nanomedicine for treatment of malignant tumors.