Dual nanoparticle immunostimulant hydrogel for synergistic combating “Cold” tumor

•The hydrogel achieved sustained release of two types of nanoparticles (NPs).•The 4T1 tumor cell-targeted NPs executed an enhanced photodynamic therapy.•The tumor-associated macrophage-targeted NPs activated the STING pathway.•Hydrogel system achieved potent treatment of “cold” triple-negative breast cancer. 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 4T1 tumor cells and tumor-associated macrophages (TAMs) for cancer cell elimination and reversal of the immunosuppressive TME. The 4T1 tumor cell-targeted NPs could specifically deliver the mitochondria-targeted photosensitizer and catalase into 4T1 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.