Immunotherapy has represented a novel and cutting-edge approach to treating patients with many types of metastatic cancers in recent years, transforming outcomes for patients who previously had limited options. Immunotherapy enhances the body’s natural defenses to target and eliminate cancer cells. The agents used are immune checkpoint inhibitors that target specific sites within the immune system, particularly focusing on T cells and their interactions with cancer cells or antigen-presenting cells.1 The primary sites at T cells of action include the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4). The US Food and Drug Administration (FDA) has approved several immunotherapy agents, and each could have different modes of action targeting these sites in various cancers. In 2020, pembrolizumab, a PD-1 inhibitor, was approved for the treatment of patients with anaplastic thyroid carcinoma.2 In 2 nonrandomized phase 2 clinical trials in this issue of JAMA Oncology, Sehgal et al3 and Cabanillas et al4 explored the applications of immunotherapy in treating patients with aggressive thyroid cancer.