Cancer pathogenesis and phase targeting through condensate fragility

Nuclear liquid-liquid phase separation (LLPS) is now recognized as a fundamental mechanism that organizes transcription and DNA repair machinery into dynamic, membraneless condensates essential for genome integrity and gene regulation. Dysregulated LLPS has emerged as a key driver of oncogenesis; yet, how pathological condensates simultaneously fuel transcriptional addiction and genomic instability remains incompletely understood. Recent biophysical and molecular advances, particularly in multivalency, concentration thresholds, and condensate material states, have revealed that cancer-associated mutations rewire phase behavior to generate hyperstable yet fragile condensates. This review explores the role of aberrant nuclear LLPS in cancer pathogenesis and therapy resistance and uniquely proposes phase targeting through condensate fragility as a precision oncology strategy, distinguishing itself by integrating oncogenic mechanisms with actionable biophysical vulnerabilities rather than focusing solely on molecular inhibition.