Novel immunogenic cell death inducer combined with autophagy inhibitor to amplify photodynamic synergistic immunotherapy for triple-negative breast cancer

Abstract Background Activating immunogenic cell death (ICD) represents a promising therapeutic strategy for tumor immunotherapy. However, photodynamic therapy (PDT)-mediated ICD effects are severely limited due to the extremely short half-life and limited diffusion radius of reactive oxygen species (ROS) hinder effective endoplasmic reticulum (ER) stress induction. In addition, targeted therapy of triple-negative breast cancer (TNBC) remain hugely challenging due to the lack of expression of multiple receptors. Results Herein, we synthesized a hierarchical targeting and controllable intelligent nanodelivery material Da-CD@CET@CQ, loaded with highly efficient ER-targeted photosensitizers CET and autophagy inhibitor chloroquine (CQ). Excitingly, Da-CD@CET@CQ NPs can selectively target TNBC tumor cells and the CET was effectively released in the tumor microenvironment, enabling local accumulation of photosensitizers in the ER and in situ ROS production, which causing stronger ER stress and amplifying the ICD effect, further increasing the immune suppression of tumor growth. More importantly, CQ released by Da-CD@CET@CQ NPs can inhibit autophagy to destroy damaged cell repair, and further enhance the anti-tumor ability of PDT. Conclusions Our findings indicate that we reported a novel strategy of photosensitizing ICD inducer to amplify ICD effects and combination with autophagy inhibition, which provides a meaningful guideline for targeted PDT synergistic immunotherapy of TNBC in the future.