Beyond Barrier Function: Tight Junctions as Dynamic Signaling Hubs Orchestrating Tumor Plasticity, Microenvironment Remodeling, and Metastatic Evolution

ABSTRACT: Tight junctions (TJs), once viewed as static paracellular seals, are now recognized as dynamic master regulators of tumor plasticity, microenvironment remodeling, and metastasis. This comprehensive review synthesizes emerging knowledge redefining TJs as versatile signaling and mechanobiological hubs. Beyond simply facilitating EMT through barrier dissolution, TJs coordinate every stage of the metastatic cascade. The review highlights how critical proteins like ZO-1 form liquid-liquid phase-separated (LLPS) condensates to nucleate junctional assembly, which is a well-characterized biophysical event, while also evaluating the proposed, yet less empirically validated, roles of these condensates in broader mechanosensing and signaling cascades. The review also evaluates classic transmembrane-to-nuclear relays, such as the ZO-1-ZONAB axis, and discusses the emerging concept of TJ-NR cross-talk, in which claudin-mediated adhesion has been proposed to modulate SFK activity and subsequent nuclear receptor phosphorylation in specific oncogenic contexts, linking cell adhesion to transcriptional plasticity. Furthermore, TJs orchestrate organotropic colonization, support the survival of circulating tumor cell clusters by resisting hemodynamic stress, and engage in mechanical cross-talk to remodel the stiffened tumor extracellular matrix. This shifting concept transforms TJs into promising clinical targets for precise network-level interference and overcoming therapeutic resistance in advanced malignancies.