Piezo1-Mediated Mechanotransduction in Cancer: A Comprehensive Up-to-Date Review of Emerging Mechanistic and Therapeutic Insights

Mechanical forces have emerged as key determinants of cancer progression, influencing cellular behavior, tumor architecture, and therapeutic response. Among mechanosensitive molecules, the ion channel Piezo1 functions as a central transducer that converts physical cues - such as extracellular matrix (ECM) stiffness, compression, and shear stress - into biochemical signals that reshape tumor cell fate. Accumulating evidence indicates that Piezo1 exerts dualistic, context-dependent roles in cancer, promoting either tumor progression or cell death depending on the mechanical landscape, tissue context, and metabolic state. Rather than focusing solely on its molecular interactions, this review provides an integrative overview of Piezo1’s context-dependent roles across diverse malignancies, including breast, ovarian, cervical, hepatocellular, gastric, colorectal, pancreatic, and brain cancers. In each setting, Piezo1 governs distinct aspects of tumor biology - ranging from epithelial - mesenchymal transition (EMT), angiogenesis, and metabolic adaptation to immune evasion and therapy resistance-through Ca²⁺ - dependent mechanotransduction. Experimental and clinical studies consistently identify PIEZO1 overexpression as a marker of poor prognosis and metastatic potential, while genetic silencing or pharmacologic modulation alters invasion, apoptosis, or ferroptosis in a tumor-type-specific manner. By consolidating evidence from structural, cellular, and translational studies, this review delineates how Piezo1 acts as a mechanobiological hub that interprets the physical landscape of the tumor microenvironment. These findings position Piezo1 as both a mechanobiological biomarker and a therapeutically actionable target whose functional impact is dictated by tissue mechanics, malignant lineage, and the surrounding microenvironmental context.