Risk model of liquid–liquid phase separation‐related genes reveals the prognosis and tumor microenvironment characteristics of colorectal cancer

Colorectal cancer (CRC) progression involves liquid-liquid phase separation (LLPS), but its prognostic significance remains unexplored. Using The Cancer Genome Atlas transcriptomic data, we developed an LLPS-based risk model that outperformed traditional clustering methods. High-risk patients exhibited worse outcomes, correlating with higher tumor mutational burden and reduced natural killer/T-cell infiltration, yet increased predicted response to immune checkpoint blockade. Drug sensitivity analysis suggested therapeutic efficacy of Entinostat and 5-fluorouracil in this subgroup. Five pivotal genes (ASXL1, DDX21, HNRNPA1L2, TACC3, and TRIM28) were identified as LLPS-driven regulators of CRC progression, mechanistically linking phase separation to epigenetic dysregulation, aberrant RNA splicing, and metabolic reprogramming. Our study provides the first LLPS-associated prognostic framework for CRC, offering both a risk stratification tool and actionable therapeutic insights. The findings highlight LLPS as a critical molecular organizer in CRC pathogenesis and a potential target for precision oncology approaches.