Radiation therapy-activated nanoparticle and immunotherapy: The next milestone in oncology?

Radiotherapy (RT) is a fundamental treatment at the locoregional or oligometastatic stages of cancer. In various tumors, RT effects may be optimized using synergistic combinations that enhance tumor response. Innovative strategies have been designed that explore the radiation mechanisms, at the physical, chemical and biological levels, to propose precision RT approaches. They consist in combining RT with immunotherapy to revert radiation immunosuppressive effects or to enhance radiation-induced immune defenses against the tumor to favor immunogenic cell death. Radiotherapy-activated nanoparticles are another innovation. By increasing radiation response in situ, nanoparticles improve tumor control locally, and can trigger systemic immune reactions that may be exploited to improve the systemic efficacy of RT. Strong clinical evidence of improved outcomes is now available for combinations of RT and immunotherapy on one hand and RT and nanoparticles on the other hand. The triple combination of RT, immunotherapy and nanoparticles is promising in terms of tolerance, local and systemic anti-tumor control. Yet, significant challenges remain to unravel the complexity of the multiscale mechanisms underlying response to this combination and their associated parameters. Such parameters include patient characteristics, tumor bulk and histology, radiation technique, energy, dose, fractionation, immunotherapy targets and predictive biomarkers, nanoparticle type, size, delivery (intratumoral/intravenous), distribution. The temporal combination is another critical parameter. The mechanisms of response of the combinatorial approaches are reviewed, with a focus on underlying mechanisms based on preclinical, translational and clinical studies. Opportunities for translation of current understanding into precision RT trials combined with immunotherapy and nanoparticles are also discussed.