A tumor microenvironment responsive biodegradable CaCO₃/MnO₂- based nanoplatform for the enhanced photodynamic therapy and improved PD-L1 immunotherapy

Abstract

The low efficiency of photodynamic therapy (PDT) is caused by tumor hypoxia and the adaptive immune resistance/evasion of tumor cells, while the currently emerging immune checkpoint therapy restores the intrinsic immune capacities but can't directly attack the tumor cells.Methods: Herein we report an integrated nanoplatform that combines PDT with immunotherapy to enhance photodynamic therapeutic effects and simultaneously inhibit tumor cells resistance/evasion. To achieve this, we fabricated Mn@CaCO3/ICG nanoparticles and loaded them with PD-L1-targeting siRNA.Results: Thanks to the protection of CaCO3 on the loaded ICG and the oxygen produced by MnO2, an enhanced photodynamic therapeutic effect in vitro was observed. In vivo experiments demonstrated that the nanoplatform could efficiently deliver the loaded drug to the tumor tissues and significantly improve tumor hypoxia, which further contributes to the therapeutic effect of PDT in vivo. Moreover, the synergistic benefits derived from the siRNA, which silenced the checkpoint gene PD-L1 that mediates the immune resistance/evasion, resulted in a surprising therapeutic effect to rouse the immune system.Conclusions: The combination treatment strategy has great potential to be developed as a new and robust method for enhanced PDT therapy with high efficiency and a powerful antitumor immune response based on PD-L1 blockade.

Photodynamic therapy regulates fate of cancer stem cells through reactive oxygen species

“…In this sense, PDT-treated melanoma cells induce IFN-1-dependent phenotype maturation of dendritic cells by enhancing costimulatory signals (CD80 and MHC-II molecules) and tumor-directed chemotaxis. Based on the discovery of enhanced immunogenicity, there have been studies combining PDT and immunotherapy, loading si-PD-L1[ 200 ], docetaxel (DTX)[ 201 ], PD-L1 monoclonal antibody[ 202 ], and anti-PD-L1 peptide[ 203 ], among others, to enhance the antitumor effect.…”

Harnessing nanomedicine to overcome the immunosuppressive tumor microenvironment

“…Anti-PD-L1 [172,173] Anti-PD-1 [174] PD-L1 silencing siRNA [175] CpG [176,177] Hyperthermia therapy High temperature (40-45°C) generated locally by light, magnetic field, radiation or microwave causes tumor cell death, provoking antitumor immunity [178].…”

“… Photodynamic therapy combined with immune adjuvant or checkpoint regulator to promote immunological response and antigen presentation. Anti-PD-L1 [ 172 , 173 ] Anti-PD-1 [ 174 ] PD-L1 silencing siRNA [ 175 ] CpG [ 176 , 177 ] Hyperthermia therapy High temperature (40–45 °C) generated locally by light, magnetic field, radiation or microwave causes tumor cell death, provoking antitumor immunity [ 178 ]. Hyperthermia therapy combined with immune adjuvant, checkpoint regulator, or CAR-T therapy.…”

Cancer photo-immunotherapy: from bench to bedside

“…Based on their synergistic thermal-immuno effects, combinations of photothermal agents and immunoadjuvants (e.g., LPS, CpG, R848) or cytokines (e.g., GM-CSF, G-CSF) as endogenous vaccinations have been developed in recent years 24 - 27 . In addition, the introduction of checkpoint inhibitors (e.g., antibodies against PD‐L1 (programmed cell death-ligand 1), antibodies against CTLA-4 (cytotoxic T lymphocyte-associated antigen-4), small molecule IDO inhibitors (indoleamine 2,3-dioxygenase)) after phototherapy has been shown to markedly improve treatment efficacy by blocking the immunosuppressive receptors on the cell surface, thereby restoring the cytotoxic function of tumor-specific T-cells 28 , 29 .…”