This integrated paradigm demonstrates compelling clinical translation: TLR9 agonist vidutolimod nanoparticles achieved 25% objective response in PD-1-resistant melanoma with immunologically cold phenotypes, while Mn2+-STING nanoformulations combined with anti-PD-1 elicited 45.5% response in therapy-refractory metastatic tumors. Here, STING1 is linked to metastatic neoplasm.