From molecular bridges to therapeutic targets: the pivotal role of liquid-liquid phase separation in tumors and new frontiers in targeted therapy

Abstract Liquid-liquid phase separation (LLPS) enables biomolecules to form dynamic membraneless condensates that organize biochemical reactions in space and time. In cancer, this adaptive organizational principle is frequently hijacked, transforming reversible regulatory assemblies into persistent hubs that sustain malignant cell states. In this Review, we propose a conceptual and translational framework that links molecular regulation, condensate dynamics, material-state transitions, tumor phenotypes, and therapeutic vulnerabilities. We discuss how post-translational modifications and environmental cues reshape phase behavior, and how aberrant LLPS coordinates cancer-associated programs, with particular emphasis on metabolic reprogramming, immune regulation, autophagy, deoxyribonucleic acid (DNA) damage repair, and therapy resistance. Beyond conventional tumor-intrinsic condensates, we highlight two relatively underexplored dimensions of LLPS biology: material-state transitions toward gel- or solid-like states, and gut microbiota–associated phase biology linking microbial signals to host condensate-forming pathways. We further distinguish experimentally supported interactions from indirect or incompletely validated microbiota-mediated effects on host phase behavior. Finally, we discuss therapeutic opportunities arising from LLPS biology, including strategies to disrupt oncogenic condensates, reprogram phase behavior, induce cytotoxic or immune-favorable condensate states, and engineer LLPS-based delivery or signaling platforms. Collectively, this review positions LLPS as a unifying framework for understanding tumor evolution and as a programmable therapeutic principle for next-generation precision oncology.