Next-generation cancer immunotherapy increasingly recognizes the tumor microenvironment (TME) as a decisive regulator of therapeutic efficacy and durability. While immune checkpoint blockade and other immunotherapies have achieved remarkable clinical success, sustained benefit remains limited to a subset of patients, underscoring the insufficiency of immune activation alone. Accumulating evidence reveals that the TME functions as a dynamic immune ecosystem that shapes immune cell infiltration, metabolic fitness, spatial organization, and effector function. Static or reductionist biomarker frameworks fail to capture the temporal and functional heterogeneity of TME states that govern immunotherapy sensitivity and resistance. Importantly, immunotherapeutic interventions themselves induce adaptive TME remodelling, frequently triggering compensatory immunosuppressive circuits and acquired resistance. In this review, we synthesize recent advances in understanding functional and evolving TME states and discuss how strategic modulation of the microenvironment can enable more durable and context-dependent immunotherapy responses. By reframing immunotherapy as a process of TME state management rather than isolated immune stimulation, this perspective outlines guiding principles for designing adaptive, TME-driven immunotherapeutic strategies.
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.
