URMylation Signaling Pathway in Cancer: Molecular Mechanisms and Therapeutic Opportunities.

Ubiquitin-related modifier 1 (URM1) defines a distinctive ubiquitin-like system in which URM1 functions both as a covalent protein modifier and a sulfur carrier required for wobble uridine (U34) thiolation of cytosolic tRNAs. This dual role places URM1 signaling at the intersection of protein post-translational modification and codon-sensitive translational control. Although URM1 remains less well characterized than ubiquitin and other ubiquitin-like modifiers, accumulating evidence links URM1-associated processes to oxidative-stress tolerance, proteostasis, and tumorigenesis. In this review, we summarize the molecular architecture and biochemical regulation of URM1 signaling, distinguish the biological significance of protein URMylation from URM1-dependent tRNA U34 thiolation, and evaluate evidence connecting these pathways to cancer biology. Notably, stress-inducible protein URMylation has been demonstrated in mammalian cells, although endogenous mammalian URM1 substrates and their cancer-relevant functions remain incompletely defined to date. In parallel, URM1-dependent tRNA thiolation has been linked to selective translational programs that support metastatic progression and adaptation to targeted therapy. We further discuss emerging therapeutic opportunities associated with redox and translational dependencies, as well as the potential limitations and challenges of pathway selectivity, biomarker development, and normal-tissue toxicity. Together, these studies position URM1 signaling as a context-dependent stress-adaptive network with emerging relevance to cancer biology and precision oncology.