Radio‐immunotherapy has offered emerging opportunities to treat invasive melanoma due to its immunostimulatory performances to activate antitumor immune responses. However, the immunosuppressive microenvironment and insufficient response rate significantly limit the practical efficacy. This study presents an autologous cell‐derived exosomes (Exo)‐engineered nanoagonist (MnExo@cGAMP) containing with metalloimmunotherapeutic agent (Mn2+ ions) and nucleotidyltransferase (2′,3′‐cGAMP, a STING agonist) for boosting melanoma‐targeted radio‐immunotherapy by cascade cGAS‐STING pathway activation. The MnExo@cGAMP can efficiently accumulate in tumor cells due to the autologous targeting performance. Once internalized by tumor cells, the released Mn2+ ions will enhance stimulator of interferon gene (STING) binding and sensitize cyclic GMP‐AMP (cGAS) to radiotherapy‐induced double‐straned DNA (dsNDA), resulting in amplification of cGAS‐STING pathway activation together with X‐ray irradiation. Meanwhile, loaded 2′,3′‐cGAMP can directly augment pathway activity acting as a secondary messenger. These cascade activations of cGAS‐STING pathway trigger the overexpression of type I interferon, promote dendritic cells (DCs) maturation, antigen presentation, and increase CD8+ T cell activation, resulting effective radio‐immunotherapeutic outcome by overcoming immune‐suppression in melanoma. This study demonstrates a targeted therapeutic modality involving metalloimmunotherapy and agonist for efficient melanoma radio‐immunotherapy by cascade cGAS‐STING pathway activation.
