Co-encapsulation of an AKT Inhibitor Enhances the Tumor-cell Selectivity of STING Agonists in Co-delivery Liposomes

The therapeutic potential of STING agonists in cancer immunotherapy is hindered by poor tumor selectivity, resulting in systemic inflammation. Conventional targeted delivery strategies rely on cell-surface markers, which inadequately distinguish tumor from normal cells. Here, we propose an intracellular-protein-guided approach to achieve tumor selective STING activation.

Leveraging the elevated phosphorylated AKT (p-AKT) levels characteristic of tumor cells, we engineered a synergistic co-delivery liposomal platform to selectively enhance STING agonist activity within tumors. Hydroxypropyl-β-cyclodextrin (HPβCD) liposomes were used to co-encapsulate resveratrol (Res), a mild, natural STING agonist, and curcumin (Cur), an AKT inhibitor, enabling simultaneous tumor targeting and AKT inhibition-mediated amplification of STING signaling.

The co-loaded HPβCD liposomes achieved potent, tumor-selective STING activation enhanced by AKT inhibition. In vitro, this system reduced tumor cell proliferation by > 60% compared to controls. In vivo, Cur pretreatment markedly amplified Res-induced STING signaling, eliciting robust adaptive immune responses, suppressing metastatic recurrence, and extending median survival from 35 to 85 days (p < 0.05) relative to monotherapy groups.

This study demonstrates that combining AKT pathway inhibition with STING activation offers a powerful, tumor-selective immunotherapy approach. By leveraging intracellular biomarkers rather than surface antigens, the co-delivery liposomal system achieves potent immunomodulation with minimal off-target effects, highlighting its potential as a next-generation strategy for precision cancer immunotherapy.