Noninvasive Transdermal Delivery of STING Agonists Reshapes the Immune Microenvironment of Melanoma and Potentiates Checkpoint Blockade Therapy Efficacy

The emergence of immunotherapy as a revolutionary therapeutic modality has fostered confidence and underscored its potent efficacy in tumor therapy. However, enhancing the therapeutic efficacy of immunotherapy by precise and judicious administration poses a significant challenge. In this context, we have developed a disulfide-bearing transdermal nanovaccine by integrating a thiol-reactive agent lipoic acid (LA) into a metal-coordinated cyclic dinucleotide nanoassembly, designated as LA-Mn-cGAMP (LMC) nanovaccines. Upon topical application to the skin with melanoma, the dithiolane moiety of LA enables thiol–disulfide dynamic exchange in the skin, hence facilitating penetration into both the skin and subcutaneous tumor tissues via the thiol-mediated uptake (TMU) mechanism. Our findings demonstrate that transdermal administration of LMC significantly enhances STING activation, mitigates the immunosuppressive tumor microenvironment (TME), and retards melanoma progression. Moreover, the remodeled TME amplifies the efficacy of immune checkpoint inhibitors. This advancement offers an administration strategy for existing STING agonist therapy, potentially improving the biosafety of immunotherapy.