The exclusion of immune cells from the tumor can limit the effectiveness of 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 the production of type I interferons (IFNs), facilitating the maturation of dendritic cells (DCs) and the function of T cells. Although the increased expression of programmed death-ligand 1 (PD-L1) 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 a STING agonist (Vadimezan, abbreviated to Vad) and a PD-L1 inhibitor (BMS-1). Losartan was first released in the acidic tumor microenvironment to overcome the physical barrier, enhancing the penetration of immunotherapeutic components. Under the triggering of 1O2 generated by a photosensitizer (Ce6), the reactive oxygen species (ROS)-sensitive degradation of the nanocore ensured the site-directed release of Vad and BMS-1. The released Vad and damaged tumor DNA activated immune responses through the 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 of immune effector cells, and lower tumor volume were observed in this integrated triple drug sequential therapy, which provides a promising prospect for TNBC treatment.
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