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.　©　2025　American　Chemical　Society.