Targeting UFMylation in Cancer: Emerging Roles in Cancer Stem Cell Regulation and Therapeutic Targeting

UFMylation is an emerging ubiquitin-like post-translational modification involved in protein quality control, endoplasmic reticulum (ER) homeostasis, and cellular responses to stress. Increasing evidence links UFMylation to cancer development and progression, revealing tumor-promoting and tumor-suppressive functions that depend on tumor type, cellular context, and the substrates involved. Recent discoveries also implicated UFMylation in cancer stem cell (CSC) maintenance, particularly through its effects on stemness-associated signaling pathways, transcription factors, tumor sphere formation, and therapeutic resistance. This review outlines the molecular mechanisms and regulation of UFMylation and examines its context-dependent functions in cancer, with particular emphasis on CSC biology. We discuss how alterations in the UFMylation pathway may influence stem-like properties and treatment responses. We also examine therapeutic strategies for targeting the UFMylation pathway, including pharmacological inhibitors, modulation of transcription factors, and combination approaches aimed at improving treatment responses. Particular attention is given to the potential of inducing ferroptosis through UFMylation inhibition as a strategy for targeting CSCs. Finally, this review highlights principal knowledge gaps and future research directions, emphasizing the need to characterize novel relevant substrates, validate observations in physiologically accurate settings, and implement in vivo tumor models to better understand the role of UFMylation in cancer stemness.