Pyroptosis of Breast Cancer Stem Cells and Immune Activation Enabled by a Multifunctional Prodrug Photosensitizer

Abstract

AbstractBreast cancer stem cells (CSCs) are responsible for the occurrence, resistance, recurrence, invasion, and metastasis of tumors. However, even trace amounts of CSCs may lead to tumor resistance and recurrence, which fundamentally reduces the therapeutic efficiency of numerous anticancer drugs. Thus, the development of a therapeutic agent that can reduce the tumorigenicity of CSCs and overcome tumor resistance and recurrence is essential. Here a novel multifunctional prodrug T‐P is reported as a photosensitizer, which links phenothiazine drug with the synthesized aggregation‐induced emission photosensitizer T‐C via an ester bond. Importantly, this photosensitizer is found to be able to induce the pyroptosis of breast CSCs as well as to activate their death pathway protein phosphatase 2A to inhibit CSCs and systemic anti‐tumor effects. T‐P can rapidly target mitochondria and overlap with lysosomes after mitochondrial escape, and it can cause mitochondrial and lysosomal dysfunction. It releases reactive oxygen species through photoactivation, triggering pyroptosis‐mediated strong anti‐tumor immune response. On the 5th day of in vivo therapy of breast cancer, the primary tumor is eliminated and the growth of distant tumors is also inhibited. This research would provide an impetus as well as a new strategy for CSCs‐targeted cancer photoimmunotherapy and beyond.