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) <i>in vitro</i> 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.