Engineered GLUT1-targeted STING polyproagonists: Redox-triggered activation and enhanced endosomal escape for cancer immunotherapy.

The stimulator of interferon genes (STING) pathway plays a critical role in bridging innate and adaptive antitumor immunity, representing a promising target in cancer immunotherapy. However, the clinical application of STING agonists is limited by poor pharmacokinetics, low cytosolic delivery efficiency, and immune-related adverse effects. To address these challenges, we developed STING polyproagonist nanoparticles (named GA+S@SR) by self-assembly of an amphiphilic diblock copolymer, P(OEGMA-co-GAMA)-b-PSSRMA, combined with POEGMA-b-P(DEAEMA-co-BMA). The galactose (GA) moieties enable targeted delivery to glucose transporter 1 (GLUT1) on tumor cells, facilitating cellular internalization. The P(DEAEMA-co-BMA) segments promote endosomal escape, followed by the release of the disulfide-linked SR-717 in the cytosol under reducing conditions. This leads to robust activation of the STING pathway, resulting in dendritic cell maturation, enhanced T-cell infiltration, and potent antitumor immunity. Furthermore, when combined with an αPD-L1, this polyproagonist synergistically enhances the efficacy of immune checkpoint blockade, effectively inhibiting primary and distant tumors by counteracting immune evasion. This study highlights the potential of STING polyproagonists in achieving effective cytosolic delivery of STING agonists to boost antitumor immunity and overcome current limitations associated with STING immunotherapy.