Abstract: Shimon Sakaguchi, a Japanese scientist, together with Mary E. Brunkow and Fred Ramsdell, American scientists, were jointly awarded the 2025 Nobel Prize in Physiology or Medicine for their pioneering discoveries in the field of peripheral immune tolerance. This review summarizes the Nobel Prize-winning research on immune tolerance and discusses the development, functions, and therapeutic applications of regulatory T cell (Treg)-based interventions. These seminal studies on immune tolerance underscore a central immunological concept—a healthy immune system relies not only on its robust capacity to eliminate pathogens and mutated cells, but also on the precise inhibitory (or “brake”) and tolerance mechanisms. This concept will help deepen our understanding of key medical challenges such as autoimmune diseases, transplant rejection, and tumor immunity. It will spur the development of a series of therapeutic strategies targeting peripheral immune tolerance and Treg cells and advance research in precision immune regulation.