Amplifying X-ray-Induced Charge Transfer Facilitates Direct Sensitization of Photosensitizers in Radiotherapy

X-ray-induced photodynamic therapy offers substantial promise for treating deep-seated tumors, but it is still limited by highly inefficient energy transfer processes and the stringent requirements for scintillators with high luminescence quantum yield and significant singlet–triplet intersystem crossing ratios. Herein, we describe X-ray-induced electron-dynamic therapy (X-eDT), which obviates the need for intersystem crossing by exposing nonluminescent hafnium-silica nanoparticles to X-rays, to generate high-energy electrons that can sensitize lower-lying triplet states of various photosensitizers. Our approach strongly induced the production of singlet oxygen (6.18-fold) in vitro even at lower X-ray doses, and in mice it strongly inhibited the growth of xenografts derived from liver, breast, or colon cancer cell lines (CDX), and growth of patient-derived xenografts (PDX) of hepatocellular carcinoma. In these CDX preclinical systems, X-eDT was not only effective against the irradiated xenograft but also against untreated xenografts in the same animal, and these abscopal effects involved enhanced tumor infiltration by CD4⁺T cells, CD8⁺T cells, and IFN-γ-polarized M1 macrophages within the tumor microenvironment. X-eDT even stimulated the production of memory T cells that inhibited rechallenges after treatment. These findings suggest that X-eDT can be effective against primary and metastatic tumors as well as tumor recurrence, which makes it much more powerful than conventional X-PDT.