A novel modality of radiation photodynamic therapy for cancer: the combination therapy of gamma knife and Cu-Cy nanoparticle mediated photodynamic effect on liver cancer

Hepatocellular carcinoma (HCC) is an aggressive form of liver cancer. Gamma Knife is a minimally invasive treatment option for cancer, but it remains constrained by limitations such as tumor recurrence and metastatic progression. In contrast, photodynamic therapy (PDT) utilizes tumor-specific targeting while providing three clinical benefits: repeatable administration, immunomodulatory activity, and synergistic integration with systemic therapies. However, traditional PDT faces limitations in treating deep-seated tumors, such as HCC. Copper cysteamine (Cu-Cy) serves as a novel photosensitizer that can be activated directly by X-ray irradiation. Our initial studies have demonstrated that Cu-Cy can be activated by the gamma-ray emitted by the Gamma Knife, making it effective for PDT. Subsequent results showed that combining the Gamma Knife with Cu-Cy-mediated PDT can not only effectively suppress the proliferation and migration of HCC cells but also inhibit tumor growth without obvious side effects. This study substantiates the efficacy and safety of combining Gamma Knife treatment with Cu-Cy-mediated PDT for the management of HCC, while also introducing innovative theories and strategies in therapeutic approaches. Furthermore, our research offers a new perspective on the selection of excitation light sources for PDT, potentially advancing the clinical application and translational viability of Cu-Cy. • A novel modality of radiation photodynamic therapy for cancer: the combination therapy of gamma knife and Cu-Cy nanoparticle mediated photodynamic effect on liver cancer • The application of gamma ray stimulate photosensitizer mediated PDT is expected to breakthrough the limitation of traditional light source in the application of deep tumor. • Using gamma knife as clinical environment simulation is expected to promote the PDT to clinical transformation.