Dual-Blocked Immune Checkpoint-Engineered Nanocarriers Combined with Photodynamic Therapy To Enhance Immunotherapy of Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) poses a significant challenge owing to its complex pathological features and treatment resistance. In recent years, immune checkpoint blockade (ICB) therapy has shown satisfactory results in the treatment of TNBC. ICB therapy targeting T cells' inhibitory receptors and innate immune checkpoints has gradually become a research hotspot. However, a study has found that compared with single immune checkpoint inhibition, dual ICB has a more significant therapeutic effect. This study aimed to develop an engineered nanocarrier, aLS@VpNPs, loaded with the photosensitizer verteporfin and coated with TNBC cell membranes loaded with antilymphocyte activation gene-3 (anti-LAG3) and sialic acid binding immunoglobulin-like lectin 10 (Siglec10) proteins for delivering combination therapies. The biomimetic vector can mimic the surface characteristics of tumor cells, showing better biocompatibility and efficient tumor-targeting ability. Under photodynamic therapy (PDT), reactive oxygen species (ROS) are generated at the tumor site to directly kill cancer cells and induce immunogenic cell death, transforming "cold tumors" into "hot tumors" and further enhancing the efficacy of dual ICB targeting T cells and macrophages. In summary, this approach improves drug delivery efficiency and therapeutic precision and activates the host immune system through the synergistic mechanisms of PDT and ICB. In addition, the study reveals potential mechanisms for the combined therapy in modulating the tumor microenvironment, offering effective strategies and directions for TNBC treatment.