Background and Purpose: Melanoma is an aggressive cancer, and current immunotherapies like mRNA vaccines target tumor antigens to activate immune responses. However, NK cell absence limits efficacy. Gardiquimod enhances NK cell activity, and inhibiting PERK disrupts the unfolded protein response (UPR), inducing tumor apoptosis. This study develops the GD-LPR mRNA vaccine to activate dendritic cells and NK cells via Gardiquimod, combined with a PERK inhibitor (GSK) to shift macrophages to the M1 phenotype, boosting immune responses and tumor cell death. Experimental Approach: The GD-LPR vaccine, using DOTMA, delivers the Gp-100 antigen, stimulating CTLs and enhancing immune responses. It activates dendritic cells and boosts NK cell activity with Gardiquimod. When combined with the PERK inhibitor GSK, promotes apoptosis, and shifts the tumor microenvironment toward M1 macrophage, especially for subcutaneous tumors and lung metastases. Key Results: The GD-LPR vaccine effectively delivered the Gp-100 antigen, activating dendritic cells and CTLs. Gardiquimod enhanced NK cell activity, aiding tumor clearance. The combination with GSK disrupted the UPR, induced apoptosis, and shifted the tumor microenvironment to favor M1 macrophages, enhancing immune responses. This strategy shows potential for treating melanoma, particularly subcutaneous tumors and lung metastases. Conclusion and Implications: The GD-LPR vaccine activates immune responses against melanoma by delivering Gp-100, stimulating dendritic cells, CTLs, and enhancing NK cell activity with Gardiquimod. Combined with GSK, it disrupts the UPR, promotes apoptosis, and shifts the tumor microenvironment to M1 macrophages. This combination offers a promising new approach for treating melanoma, with potential for enhancing immune-based therapies. Keywords: mRNA vaccine; gardiquimod; PERK inhibitor; tumor microenvironment; melanoma