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The lipid platform increases the activity of STING agonists to synergize checkpoint blockade therapy against melanoma.

The response rate to PD-1/PD-L1 immune checkpoint inhibition (ICI) therapy in melanoma remains low due to the immunosuppressive tumor microenvironment. Novel strategies synergizing ICI treatment are urgently sought after. Activation of the stimulator of interferon genes (STING) has recently emerged as a critical pathway to overcome immunosuppression. Herein, 2'3' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), a universal STING agonist, was encapsulated into lipid nanoparticles conjugated with mannose (LP-cGAMP) for dendritic cell (DC)-specific cytosolic delivery. LP-cGAMP induced STING-related pro-inflammatory and intratumoral injections of LP-cGAMP increased DC maturation and CD8+ T cell infiltration more efficiently compared to free cGAMP. Given the upregulation of PD-L1 on tumor cells in response to STING activation, we further tested the combination therapy of LP-cGAMP and anti-PD-L1 and observed a superior antitumor effect in B16F10 and BRAF-mutated murine melanoma models. Our findings prove that targeted delivery of cGAMP can synergize PD-L1 blockade therapy in melanoma and the combinational immune therapy has a great potential to produce a long-lasting anti-tumor effect.