Photodynamic Biomimetic Liposomes Targeted to the Endoplasmic Reticulum Enhance Combined Immunotherapy for Triple-Negative Breast Cancer

Abstract

Cancer immunotherapies, such as immune checkpoint inhibitors, have advanced rapidly and achieved notable success, yet they face significant challenges due to poor response rates and immune-related adverse effects, particularly in cases of triple-negative breast cancer (TNBC). Photodynamic therapy (PDT) can initiate immunogenic cell death (ICD) by inducing endoplasmic reticulum (ER) stress, thereby enhancing the effectiveness of tumor immunotherapy. Herein, we develop potent PDT biomimetic liposomes (PB Lipo) locating the ER to realize a synergistic immuno-photodynamic treatment. The PB Lipo is prepared using the optimal ratios of the phospholipids in the ER membrane. It is then loaded with indocyanine green (ICG), a photosensitizer approved for clinical use. PB Lipo has the unique ability to accumulate in the ER via membrane fusion, leading to severe ER stress when exposed to near-infrared (NIR) laser light, thus intensifying ICD. In combination with the antiprogrammed death-ligand 1 (PD-L1) antibody (αPD-L1), PB Lipo significantly improves efficiency against tumors in xenograft TNBC models. As a result, our combined treatment enhances mature dendritic cells, activates CD4⁺ T and CD8⁺ T cells, and promotes the secretion of cytotoxic cytokines. Collectively, our findings reveal that PB Lipo-mediated PDT presents a viable approach for effectively targeting the ER and enhancing ICD, thereby boosting antitumor efficacy in TNBC.