Tumor Microenvironment Stress-Induced Phase Separation Drives Adaptive Resistance

Adaptive resistance is a major cause of cancer treatment failure. Traditional studies have largely focused on genetic mutations and clonal evolution, yet these mechanisms fail to explain rapid and reversible non-genetic adaptation. Herein, we propose that stresses within the tumor microenvironment (TME), such as hypoxia and acidosis, can rapidly assemble diverse biomolecular condensates via liquid-liquid phase separation (LLPS), including stress granules and DNA repair condensates. These structures cooperatively drive adaptive resistance by protecting key signaling and drug-target molecules, enhancing DNA damage repair, and remodeling stemness and phenotypic plasticity. Thus, phase separation emerges as a critical physical bridge linking TME stress to resistance evolution, and targeting condensates alongside microenvironmental reprogramming offers a promising strategy to overcome therapy resistance.