Mechanisms of Action of Radiotherapy and Immunotherapy in Lung Cancer: Implications for Clinical Practice

Radiotherapy (RT) remains an essential component of treatment for localized or advanced lung cancer that is not amenable to surgery. Immunotherapies such as checkpoint inhibitors have attracted much attention in recent years and offer promise for the treatment of several types of cancer; however, response rates and overall survival in patients with lung cancer remain low. Combining RT with immunotherapy is actively being explored as a way of boosting the effectiveness of both types of therapy. Here, we discuss various aspects and types of RT and their activity in combination with immunotherapy, including radiation dose and fractionation, modality (photons versus protons), and ultrahigh dose rate (FLASH) radiation. We then review the basic mechanisms of how RT interacts with immunotherapy in lung cancer in terms of the type of immune cell, e.g., CD8/CD4 T cells, Tregs, macrophages, natural killer (NK) cells, B cells, and dendritic cells. We also introduce promising new RT methods that involve “pulsed” dosing or high-dose plus low-dose RT, and their role in treating multiple isocenters of disease. We hope to provide some implications for better clinical practice.