"Intrinsic disorder-protein modification-LLPS-tumor" regulatory axis: From regulatory mechanisms to precision medicine.

Liquid-Liquid Phase Separation (LLPS) is an important mechanism for the formation of functional droplets. Protein modification is an important pathway to regulate LLPS, in which series of modifying groups realize dynamic regulation by changing the charge and spatial resistance of the modified proteins. Meanwhile, uncontrolled protein modifications associated with LLPS dysregulation are highly correlated with tumorigenesis and development, suggesting the existence of a potential regulatory axis between the three. In this review, we pioneered "protein modification-LLPS-tumor" regulatory axis and summarized protein modifications that regulate LLPS in cancer cells (including phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, lactate, ADP-ribosylation, O-glycosylation, and acylation) and their associated modification mechanisms. Finally, we outline advances in precision medicine based on this regulatory axis. The aim of this review is to expand the understanding of protein modifications regulating LLPS under normal or abnormal cellular conditions and to provide possible ideas for precision therapy.