Liquid-liquid phase separation in cancer radiotherapy and immunotherapy: emerging roles and translational opportunities

Abstract

Abstract Liquid-liquid phase separation (LLPS) is a physicochemical process through which biomolecules assemble into membraneless condensates via weak, multivalent interactions. LLPS has emerged as a central biological principle that helps explain intracellular spatiotemporal compartmentalization, signal transduction, and stress responses. Dysregulated LLPS contributes to tumor initiation, progression, immune evasion, and treatment resistance; however, its cell-type-specific functions and relevance to radiotherapy and immunotherapy remain incompletely integrated. In this review, we critically synthesize recent mechanistic and translational advances linking LLPS to cancer radiotherapy and immunotherapy. Condensates may either support therapeutic resistance and immune evasion or enhance radiosensitivity and antitumor immunity, depending on their molecular composition, subcellular localization, cell type, and treatment context. We examine how condensate regulation connects radiation-induced DNA damage repair with innate immune activation and evaluate emerging therapeutic strategies that target disease-associated condensates. We also assess LLPS-associated abnormal condensates as candidate biomarkers for prognosis and prediction of tumor response to radiotherapy and immunotherapy. Tissue-specific LLPS regulation across tumor types, dynamic condensate remodeling under therapeutic stress, and rational strategies combining phase-separation modulation with immune-checkpoint inhibitors and radiotherapy require further investigation. Integrating multi-omics data with artificial intelligence-based algorithms may help construct systematic LLPS-related therapeutic-event maps and predictive models, thereby prioritizing experimentally testable hypotheses for personalized cancer management. With rigorous mechanistic validation and prospective clinical evaluation, selective modulation of disease-associated condensates may enhance radiosensitivity and strengthen antitumor immunity.