A Responsive Cocktail Nano-strategy Breaking the Immune Excluded State Enhances Immunotherapy of Triple Negative Breast Cancer

The exclusion of immune cells from the tumor can limit the effectiveness of the immunotherapy in triple negative breast cancer (TNBC). The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway plays a crucial role in priming adaptive anti-tumor immunity through type I interferons (IFNs) production, facilitating the maturation of dendritic cells (DCs) and the function of T cells. Although the increased programmed death-ligand 1 (PD-L1) expression upon STING activation is favorable for amplifying the efficacy of immune checkpoint inhibitors (ICIs) and realizing combination therapy, the penetration barrier remains a major obstacle. Herein, we fabricated a smart-responsive nanosystem (B&V@ZB-MCL) by integrating the extracellular matrix (ECM)-degrading drug losartan with STING agonist (Vadimezan, abbreviated as Vad) and PD-L1 inhibitor (BMS-1). Losartan was first released in the acidic tumor microenvironment to overcome physical barrier, enhancing the penetration of immunotherapeutic components. Under the triggering of 1O2 generated by photosensitizer (Ce6), the reactive oxygen species (ROS)-sensitive degradation of nanocore ensure the site-directed release of Vad and BMS-1. The released Vad and damaged tumor DNA activated immune responses through cGAS-STING pathway, while the elevated expression level of PD-L1 promoted the anti-tumor effect of BMS-1. Significant degradation of collagen fibers, restoration in immune effector cells, and lower tumor volume were observed in this integrating triple drug sequential therapy, which provides a promising prospect for the TNBC treatment.