Dual nanoparticle immunostimulant hydrogel for synergistic combating “Cold” tumor

The immunosuppressive tumor microenvironment (TME) in "cold" triple-negative breast cancer (TNBC) leads to resistance to current immunotherapies. Here, we designed an in-situ hydrogel reservoir to deliver two types of nanoparticles (NPs) targeting 4 T1 tumor cells and tumor-associated macrophages (TAMs) for cancer cell elimination and reversal of the immunosuppressive TME. The 4 T1 tumor cell-targeted NPs could specifically deliver the mitochondria-targeted photosensitizer and catalase into 4 T1 tumor cells to execute an enhanced photodynamic therapy and induce immunogenic cell death. The TAMs-targeted NPs delivered the stimulator of interferon genes (STING) agonist into macrophages to activate the STING pathway, triggering a type I interferon-driven innate immune response that induces a shift to a "hot" T cell-inflamed TME. This local synergistic therapy could effectively stimulate dendritic cell activation and the continuous T-cell infiltration, thereby reprograming the immunosuppressive TME, reinvigorating a powerful anti-tumor immune response and inhibiting tumor growth and metastasis in TNBC tumor model. In addition, this study combined with immune checkpoint blockade further achieves reinforced therapeutic outcome against "cold" tumor, providing a promising hydrogel-mediated platform for treatment of TNBC.