Dual-function of proton irradiation enhances photodynamic therapy and fluorescence imaging via localized secondary electron generation at the bragg peak: a hypothesis

Photodynamic therapy (PDT) and proton therapy (PT) are established cancer treatment modalities, each characterized by distinct therapeutic advantages. PDT operates through the light-induced activation of photosensitizers (PSs), resulting in the generation of oxygen-dependent reactive oxygen species (ROS) that mediate cytotoxic effects, whereas PT provides highly conformal dose delivery in the centre of tumor with reduced irradiation of surrounding normal tissues. We hypothesize that proton irradiation may synergistically enhance PDT efficacy and fluorescence-guided imaging through proton-induced secondary electron production, increased PS excitation and ROS production, particularly within high Linear Energy Transfer (LET) regions near the Bragg peak. Following PDT, residual PS accumulated within the tumor may still be exposed to proton irradiation. At the Bragg peak, proton irradiation may therefore induce PDT-related effects through two complementary mechanisms. First, protons traveling through tissue generate Cherenkov radiation, which can excite PS molecules and promote the formation of ROS. Second, proton interactions produce abundant secondary electrons that can directly excite PSs, resulting in enhanced fluorescence emission. Emerging experimental evidence suggests that accelerated protons can directly activate PSs, increase Singlet oxygen ( 1 O₂) production, and amplify fluorescence signals, while the spatial confinement of proton dose minimizes background autofluorescence from surrounding tissues. Collectively, these mechanisms support a potential theranostic paradigm in which proton irradiation not only directly causes cytotoxic radiation damage but also potentiates photodynamic activity and imaging contrast. If validated, this concept could motivate further translational and clinical research toward the development of proton-activated PDT as an integrated strategy for improving tumor control while limiting collateral tissue damage. It should also be mentioned that proton irradiation is not biologically inert, and the known accumulation of PSs in normal tissues highlights the importance of improved tumor-to-normal tissue PS uptake ratios, optimization of treatment timing, and careful evaluation of off-target effects.