Liquid–Liquid Phase Separation in Viral Infection and Immunology

Liquid-liquid phase separation (LLPS) has emerged as a fundamental physicochemical principle that organizes macromolecules into dynamic, membraneless condensates. These assemblies are increasingly recognized as critical regulators of diverse cellular processes. Notably, both viruses and their hosts exploit LLPS to optimize their respective strategies for replication and defense, forming a dynamic interplay centered around phase separation. However, a comprehensive mechanistic understanding of how LLPS modulates the dynamic viral-host battle, and how this knowledge can be leveraged for therapeutic development, remains an active area of investigation. This review systematically explores the dual roles of LLPS in viral infection and antiviral immunity. We detail how viruses hijack LLPS to form replication factories and inclusion bodies that enhance entry, replication, and immune evasion. Conversely, we explore how host cells leverage LLPS to assemble potent immune signaling hubs, such as those nucleated by cGAS-STING, NLRP6 inflammasomes, and T/B-cell receptor microdomains, to amplify antiviral responses. Furthermore, we critically evaluate emerging therapeutic strategies that target these phase separation interfaces. By integrating recent advances across virology, immunology, and biophysics, this review establishes a unified framework for understanding and targeting LLPS in viral infectious diseases, offering new perspectives for future basic research and clinical intervention.