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 radiosensitisers increase reactive oxygen species (ROS) to enhance cytotoxicity in treated cells. This approach is limited 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 radiosensitisation. Complex 1 was synthesised 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 forty per cent of mice, demonstrating a strong abscopal effect. This work establishes metallonitrene-based, ROS-independent radiosensitisation for precision radiotherapy. Overall design: RNA-seq of CT26 tumor tissues from different groups of mice treated with Complex 1 and radiation therapy