Targeting phase separation: a new strategy to disrupt the stromal-immune axis in colorectal cancer

Colorectal cancer (CRC), as one of the malignant tumors with a high incidence globally, has a complex tumor micro-environment (TME) that plays a key role in tumorigenesis, progression, and treatment resistance. In recent years, liquid–liquid phase separation (LLPS) of biomolecules has been gradually discovered to participate in regulating the dynamic balance of the stromal-immune axis in CRC as an important mechanism for integrating intracellular and extracellular signals. LLPS drives the formation of pathogenic aggregates, reshaping the functions of cancer-associated fibroblasts (CAFs), endothelial cells (ECs), and immune cells, promoting tumor cells to evade immune surveillance and forming an immunosuppressive microenvironment. Current research reveals the core role of LLPS in the malignant interactions between CRC stroma and immune cells, but how to precisely target these phase-separated aggregates remains a challenge. This article reviews the regulatory mechanisms of the stromal-immune axis mediated by LLPS, focusing on innovative therapeutic strategies based on small molecule inhibitors, protein degradation technologies, and nano-drug delivery systems, aiming to provide new theoretical basis and clinical translation directions for precise immunotherapy of CRC, and to promote overcoming the challenges of treatment resistance and recurrence.