X-ray activated platinum complex induces DNA damage and enhances cancer immunotherapy through abscopal effect

Radiotherapy is used in more than half of cancer patients, yet most radiosensitizers increase reactive oxygen species (ROS) to enhance cytotoxicity in treated cells. This approach has limited use in hypoxic tumours and may cause oxidative injury to healthy tissues. We developed a platinum(II) azido complex (Complex 1) that releases platinonitrene upon X-ray exposure. Platinonitrene reacts with nucleophilic sites on DNA bases, forming covalent adducts that disrupt DNA integrity and cause double-strand breaks, leading to tumour cell death through a mechanism distinct from classical platinum coordination. Computational modelling elucidated this pathway and supported its role in radiosensitization. Complex 1 was synthesized by sequential ligand exchange of potassium tetrachloroplatinate with cyclohexanediamine, silver nitrate and sodium azide. In murine models, complex 1 showed negligible toxicity to major organs and normal immune cells while selectively reducing regulatory T-cell infiltration in tumours. Combined with low-dose radiotherapy and programmed cell death protein 1 blockade, it achieved complete regression of bilateral tumours in 40% of mice, demonstrating a strong abscopal effect. This work establishes metallonitrene-based, ROS-independent radiosensitization for precision radiotherapy.