The roles of LLPS in transcription and chromatin organization in oncofusion-driven cancers

Liquid–liquid phase separation (LLPS) has emerged as a fundamental principle of cellular organization, enabling dynamic and reversible compartmentalization of biochemical processes without membrane boundaries. In cancer, dysregulation of LLPS is increasingly recognized as a mechanism that alters transcriptional control and chromatin architecture. Among the diverse genetic alterations observed in tumors, oncogenic gene fusions represent a particularly powerful and mechanistically distinctive class of LLPS drivers. By recombining intrinsically disordered regions with chromatin-associating domains, fusion proteins are uniquely positioned to nucleate aberrant nuclear condensates at specific genomic loci. Here, we review how fusion-driven condensates reshape gene regulation across multiple spatial scales. At the transcriptional level, these assemblies concentrate transcriptional machinery at enhancers and promoters, modulating gene activation or repression. At the chromatin level, fusion condensates recruit chromatin-remodeling complexes and histone-modifying enzymes, altering chromatin accessibility, epigenetic landscapes, and enhancer function. In certain contexts, LLPS further enables long-range chromatin interactions that rewire three-dimensional genome organization. We discuss emerging evidence distinguishing when LLPS is essential for fusion protein activity versus when it amplifies preexisting regulatory functions. Furthermore, we highlight how condensate composition, dynamics, and genomic context shape oncogenic outcomes. Finally, we consider the implications of these insights for therapeutic targeting, positioning fusion-driven condensates as promising, cancer-specific vulnerabilities and powerful model systems for defining the causal roles of LLPS in gene regulation.