UFMylation System: Biological Functions, Molecular Mechanisms, Diseases, and Drug Discovery.

UFMylation, a novel ubiquitin-like modification, plays a critical role in various intertwined cellular processes, such as the immune response, DNA damage repair, unfolded protein response (UPR), autophagy, endoplasmic reticulum (ER)-phagy, stem cell self-renewal, apoptosis, and metastasis. Dysfunction of UFMylation has been implicated in a variety of human diseases, including neurogenesis, hematopoiesis, liver development, and cancer. While this field is just emerging, research on UFMylation has escalated rapidly in recent years, with great advances having been made. However, only a few substrates of UFMylation have been identified so far, and the biological functions as well as the molecular mechanisms of the UFMylation system in tumorigenesis and the tumor microenvironment remain poorly understood. In this review, we first summarize current knowledge of the components, biochemical peculiarities, and working principles of the UFMylation system. Second, we provide a multidisciplinary review of the cellular functions, molecular mechanisms, and pathophysiological roles of the UFMylation system, with a particular emphasis on the intricate relationship between UFMylation and cancer. Finally, we discuss the potential of targeting UFMylation in cancer treatment and highlight outstanding questions for future investigation in this field.