Protein Phase Separation and Regulatory Mechanisms of Transcriptional Programming in Tumor Microenvironment in Stress Response

Abstract

Malignant tumor evolution is governed by its symbiotic relationship with the tumor microenvironment, which features steep oxygen and acidity gradients that drive malignant progression. Traditional biochemical frameworks fail to adequately explain the rapid, coordinated genomic alterations under such stresses. This review focuses on liquid-liquid phase separation (LLPS), which acts as a biophysical switch regulating transcriptional programming. The study demonstrates that tumor microenvironmental stress directly modulates the phase behavior of intrinsically disordered proteins, forming transcriptional condensates. These condensates partition transcriptional machinery, condense super-enhancer regions, and amplify oncogenic expression. Key factors analyzed include c-Myc and YAP, establishing a physical environment–LLPS–transcriptional program axis that mediates tumor adaptation. Additionally, condensed-state physical properties induce non-genetic heterogeneity and chemotherapy resistance. This work introduces a novel therapeutic strategy combining molecular antagonism with physical state intervention, offering new approaches for previously intractable transcriptional drivers. It also underscores the value of measuring protein aggregate dynamics in improving prognosis for advanced malignancies.