Synergetic photoimmunotherapy with dual-inhibition of EZH2/Akt

Abstract

The immunosuppressive state of the tumor microenvironment (TME) represents a major obstacle to achieving optimal therapeutic efficacy in breast cancer. The combination of photothermal therapy (PTT) with inhibitors marks a novel breakthrough in cancer treatment. In this study, we developed a new nanoplatform (B-Nb₂O_5−x@DA@E/A) to address the weak immune response within the tumor microenvironment (TME) of breast cancer. This novel nanoplatform is composed of oxygen-defective Nb₂O_5−x doped boron (B-Nb₂O_5−x), a linker of dopamine, an EZH2 inhibitor (EZH2i) and an Akt inhibitor (Akti). This design enables efficient delivery of the drugs directly to the tumor site while minimizing premature decomposition. Moreover, it achieves synergistic therapeutic effects in combination with PTT. We demonstrated that this approach not only induces physical destruction of tumor cells, but also generates reactive oxygen species (ROS) and O₂ locally at the irradiation site, thereby alleviating tumor hypoxia. Furthermore, the combination therapy reshapes the immunosuppressive microenvironment, promotes dendritic cell (DC) maturation and CD8⁺ T cell infiltration, and stimulates the release of immune cytokines such as IFN-γ and Granzyme B, ultimately activating a systemic anti-tumor immune response. Overall, our findings show considerable potential and open new avenues for advancing cancer therapy.