Endoplasmic Reticulum-Targeted Photodynamic Therapy Combined with Autophagy Inhibition to Enhance Synergistic Immunotherapy for Triple-Negative Breast Cancer

Graphical Da-CD@CET@CQ NPs can accurately target tumor cells, and the ER-targeting photosensitizer CET can be used as an ICD inducer for amplifying the ICD effect. Meanwhile, the ER PDT was further strengthened by autophagy inhibition, which can achieve more effective autophagy-regulated photodynamic synergistic immunotherapy for triple-negative breast cancer. Activating immunogenic cell death (ICD) represents a promising therapeutic strategy for tumor immunotherapy. However, photodynamic therapy (PDT)-mediated ICD effect is severely limited due to the extremely short half-life and limited diffusion radius of reactive oxygen species (ROS), hindering effective endoplasmic reticulum (ER) stress induction. In addition, targeted therapy of triple-negative breast cancer (TNBC) remains hugely challenging due to the lack of expression of multiple receptors. Herein, we constructed a hierarchical targeting and controllable intelligent nanodelivery material Da-CD@CET@CQ based on poly- β -cyclodextrin with remarkable solubility and stability, loaded with a novel photosensitized ICD inducer, CET, and autophagy inhibitor chloroquine (CQ). Excitingly, Da-CD@CET@CQ NPs can accurately recognize TNBC tumor cells under the mediation of SRC protein. Moreover, CET could achieve observable enrichment in the ER and amplify the ICD effect by in situ ER PDT, which is further strengthened by the autophagy inhibition caused by CQ. All results show that Da-CD@CET@CQ NPs exhibited excellent targeting ability to tumor cells and ER and effectively enhanced synergistic immunotherapy of in situ ER PDT combined with autophagy inhibition, which significantly inhibited tumor growth and metastasis. Overall, our study provides a novel strategy and meaningful guideline for targeted-PDT-synergistic immunotherapy of TNBC.