Endoplasmic Reticulum-Targeted Biomimetic Nanoparticles Potentiate the Immunotherapy of Triple-Negative Breast Cancer by Improving Immunogenicity and Eliminating Immune Resistance.

Low immunogenicity and immune resistance are insurmountable obstacles for triple-negative breast cancer (TNBC) immunotherapy. Here, we prepared endoplasmic reticulum membrane (EM)-coated, carrier-free nanoparticles (EM@CAJ) to simultaneously solve these obstacles. Benefiting from homologous EM decoration, EM@CAJ mainly relied on the intracellular endosome-Golgi-endoplasmic reticulum (ER) transport pathway, evading lysosomal degradation and achieving the precise delivery of drugs at the ER. At the ER site, chlorin e6 (Ce6) with laser irradiation induced efficient immunogenic cell death (ICD) via focused ROS-based ER stress, enhancing the immunogenicity of TNBC. However, this cascaded antitumor immune response inevitably caused immune resistance of the tumor through upregulating programmed cell death-1 ligand (PD-L1). JQ1 conveniently entered the adjacent cell nucleus and prevented induced PD-L1 production at the transcriptional level. Meanwhile, avasimibe (AVA) inhibited acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1) at the ER and regulated cholesterol metabolism to accelerate existing PD-L1 degradation, which synergized with JQ1 to doubly eliminate immune resistance. Besides degrading PD-L1, the cholesterol metabolism regulation of AVA could also downregulate integrin αV expression to inhibit tumor metastasis. Therefore, by improving immunogenicity, eliminating immune resistance, and downregulating integrin αV, these synergistic therapeutic strategies efficiently inhibit primary tumor and pulmonary metastasis in orthotopic TNBC.