Uncovering the silent invaders: Dormant tumour cells in the brain microenvironment.

Brain metastasis remains a lethal clinical challenge, largely driven by dormant tumour cells (DTCs). This reversible quiescent state enables disseminated cancer cells to evade conventional therapies and eventually cause relapse. This review provides an in-depth overview of the mechanisms through which the unique brain microenvironment orchestrates the dormancy plasticity. We summarize the multicellular crosstalk between brain DTCs and brain resident cells, including astrocytes, microglia, neurons, stromal cells and fibroblasts. The stiffness, degradability and adhesion cues of the brain extracellular matrix (ECM) act as biomechanical switches that critically determine the dormant fate of brain DTCs. Moreover, brain DTCs possess intrinsic self-regulatory programs that leverage epigenetic, metabolic and immune-evasion mechanisms to control their transition between quiescence and proliferation. Despite considerable therapeutic challenges, emerging strategies such as niche-targeting therapies and artificial intelligence-driven computational models offer promising avenues for eradicating dormant reservoirs. A deeper understanding of these complex interactions is essential for developing novel interventions to prevent brain metastatic recurrence driven by DTCs and ultimately improve patient survival.