Liquid-Liquid Phase Separation in Cancer Drug Resistance: Mechanisms and Therapeutic Opportunities

Liquid-liquid phase separation (LLPS) is an emerging biophysical principle that governs subcellular organization through the formation of dynamic, membraneless biomolecular condensates. This review aims to elucidate the multifaceted mechanisms by which dysregulated LLPS drives cancer drug resistance and to explore therapeutic strategies targeting oncogenic biomolecular condensates for improved anticancer outcomes. We synthesize evidence demonstrating that dysregulated LLPS drives cancer drug resistance through diverse mechanisms, including sustaining oncogenic transcription despite targeted therapies, creating physical barriers against chemotherapeutics, modulating immune checkpoint activity, enhancing DNA damage repair, promoting cancer stemness and radioresistance. By integrating insights from cell cycle control, cytoskeletal dynamics, and critical tumor signaling pathways, we highlight the pervasive role of LLPS in facilitating adaptive tumor responses. We also discuss how multi-omics approaches and advanced biophysical techniques facilitate studies of condensate dynamics and prognostic signature identification. Finally, we address the challenges and opportunities in developing therapeutic strategies that target oncogenic condensates, a promising approach to counteract resistance and improve anticancer treatments.