Mechanisms of Action of AGuIX as a Pan-Cancer Nano-Radiosensitizer: A Comprehensive Review.

Objective: This review provides an overview of the current knowledge regarding the mechanisms of action of AGuIX, a clinical-stage theranostic nano-radiosensitizer composed of gadolinium. It covers the steps following the administration, from the internalization in tumor cells to the interaction with X-rays and the subsequent physical, chemical, biological, and immunological events. Results: After intravenous injection, AGuIX accumulates in tumors through the enhanced permeability and retention (EPR) effect, and its specific retention properties allow its persistence in tumors for several days. At the cellular level, the nanomedicine is internalized by endocytic processes and mainly located in the cytoplasm, especially in lysosomes. AGuIX enhances the effects of radiotherapy (RT) at several levels, starting from radiation-matter interactions to a chemical stage of reactive oxygen species (ROS) production, followed by a cascade of biological events leading to tumor cell death and immune response. Indeed, AGuIX induces a local increase in radiation dose deposition through the emission of Auger electrons, leading to a subsequent increase in ROS generation. AGuIX also impacts RT-induced biological mechanisms, including DNA damage and cell death mechanisms such as apoptosis, autophagic cell death, and ferroptosis. Last, the combination of AGuIX and RT stimulates an antitumor immune response through the induction of immunogenic cell death (ICD), the activation of dendritic and T cells, and the reprogramming of tumor-associated macrophages (TAMs) into a pro-inflammatory phenotype. Conclusions: AGuIX is a clinical-stage nanoparticle (NP) intravenously administered with pan-cancer potential due to its specific biodistribution properties and a strong ability to amplify RT-induced mechanisms.