Nanoparticle-Mediated Radiotherapy Remodels the Tumor Microenvironment to Enhance Antitumor Efficacy

Radiotherapy (RT) uses ionizing radiation to eradicate localized tumors and, in rare cases, control tumors outside of the irradiated fields via stimulating an antitumor immune response (abscopal effect). However, the therapeutic effect of RT is often limited by inherent physiological barriers of the tumor microenvironment (TME), such as hypoxia, abnormal vasculature, dense extracellular matrix (ECM), and an immunosuppressive TME. Thus, it is critical to develop new RT strategies that can remodel the TME to overcome radio-resistance and immune suppression. In the past decade, high-Z-element nanoparticles have been developed to increase radiotherapeutic indices of localized tumors by reducing X-ray doses and side effects to normal tissues and enhance abscopal effects by activating the TME to elicit systemic antitumor immunity. In this review, the principles of RT and radiosensitization, the mechanisms of radio-resistance and immune suppression, and the use of various nanoparticles to sensitize RT and remodel TMEs for enhanced antitumor efficacy are discussed. The challenges in clinical translation of multifunctional TME-remodeling nanoradiosensitizers are also highlighted.