A novel Au-Se nanoplatform for co-delivery of cGAMP and acriflavine synergizes with photothermal therapy to enhance anti-tumor immunity via STING activation and HIF-1α inhibition.

Activating the stimulator of interferon genes (STING) pathway is a potent strategy for promoting tumor vascular normalization and enhancing cancer immunotherapy. However, the poor metabolic stability of classical STING agonists limits their clinical translation. Herein, we engineered a self-assembled Au-Se nanoplatform (AAC) for the co-delivery of the STING agonist cyclic 2',3'-GMP-AMP (cGAMP) and the hypoxia-inducible factor-1α (HIF-1α) inhibitor acriflavine (Acf). Upon cellular internalization, the weakly acidic tumor microenvironment (TME) triggers the synchronized release of cGAMP and Acf agents. Next, cGAMP activates the STING pathway to induce type I interferon (IFN-I) production, while Acf disrupts HIF-1α/β dimerization. The activation of STING signal pathway and the inhibition of HIF-1α/β expression synergistically suppress the expression of VEGFA and remodels the TME into an immune-permissive milieu, which promotes vascular normalization and elicits tumor immune response. Combined with the photothermal therapy (PTT) of Au nanorods, AAC induces robust immunogenic cell death (ICD), facilitates dendritic cell (DC) maturation, and enhances cytotoxic T lymphocytes (CTLs) infiltration. In murine breast cancer models, AAC effectively suppressed both primary and distant tumors, highlighting its potential as a versatile nanotherapeutic platform for synergistic photothermal enhanced immunotherapy.