Optimizing the Treatment Schedule of Radiotherapy Combined With Anti-PD-1/PD-L1 Immunotherapy in Metastatic Cancers.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1), and programmed cell death ligand-1 (PD-L1) have been approved for a variety of malignant tumors and are widely used to treat patients with metastatic disease. However, the efficacy of PD-1 inhibitors is limited due to tumor heterogeneity, high tumor burden, and "cold" tumor microenvironment. Radiotherapy can improve the anti-tumor effects of PD-1/PD-L1 inhibitors in various ways. As a new radiotherapy method, stereotactic body radiotherapy (SBRT) or hypofractionated radiotherapy (HFRT) provides higher doses per fraction to the target lesions, thus achieving immune activation effects and overcoming tumor resistance to anti-PD-1/PD-L1 treatment, which significantly improves the local and distant control of tumors. However, for different metastatic situations, radiotherapy plays different roles in the combination therapy. In oligometastatic status, radiotherapy can be used as a local radical treatment aiming to eliminate cancers in cooperation with systemic PD-1 inhibitors. In other circumstances, like bulky metastasis or multiple metastatic tumors, radiotherapy can be used as adjuvant to systemic immunotherapy. This review focuses on the underlying mechanisms and optimization strategies for the combination of radiotherapy and anti-PD-1/PD-L1 therapy in metastatic disease.