Precancerous microenvironment: A signalling perspective

The progression from healthy tissue to malignancy involves a critical precancerous stage marked by cellular lesions with aberrant molecular and phenotypic characteristics. The fate of these lesions is shaped not only by cell-intrinsic alterations but also by the precancerous microenvironment (PME), an ecosystem of epithelial, stromal and immune cells embedded within the extracellular matrix. Focusing on epithelial precancers, this review first defines the metastable state and signalling networks that distinguish precancer from homeostasis and cancer. It then examines the models and technologies used to investigate PME signalling across spatial-temporal dimensions, followed by an integrated overview of how PME components collectively shape lesion trajectories. Finally, it outlines the outstanding questions and research priorities needed to advance mechanistic insight and realise the translational potential of PME-targeted interventions.