An Anisotropic Gold‐Palladium Heterostructured Nanosystem for Synergistically Overcoming Radioresistance and Enhancing Melanoma Radioimmunotherapy

Radiotherapy (RT) has recently reemerged as a promising approach for melanoma treatment because of its potential to trigger abscopal effects. However, the intrinsic radioresistance of melanoma significantly diminishes RT-induced DNA damage and the subsequent release of immunostimulatory molecules, thereby impairing systemic antitumor immunity. To overcome these challenges, a multifunctional anisotropic Au-Pd heterostructured nanosystem (APSMR) is developed that incorporates a plasmonically enhanced Au-Pd core, with a shell composed of a biodegradable, Mn-doped targeting peptide. The nanosystem integrates photothermal, radiotherapeutic, and immunomodulatory functions. Under 1064 nm laser irradiation, APSMR generates reactive oxygen species (ROS) via plasmon-driven catalysis and Mn-mediated Fenton-like reactions. Concurrently, mild hyperthermia (HT) promotes oxygenation and disrupts DNA repair pathways, resulting in multi-directional DNA damage and an increase in immunogenic cell death (ICD). Furthermore, the release of Mn²⁺ ions activates the cGAS-STING pathway, which synergizes with ICD to promote systemic antitumor immunity. Notably, APSMR treatment also upregulates PD-L1 expression, thereby sensitizing tumors to immune checkpoint blockade. Collectively, APSMR offers a potent and synergistic strategy to amplify RT-driven tumor vaccination and improve therapeutic responses against metastatic melanoma.