PIEZO2 in tumors: from mechanobiological switches to activity-targeted therapies

Mechanosensitive ion channel PIEZO2 translates microenvironmental forces into Ca²⁺-dependent signals that shape tumor behavior. Across cancers, PIEZO2 exhibits context-dependent roles, with evidence for both pro- and anti-tumor functions, depending on tissue type, molecular subtype, disease stage, and stromal context. This review synthesizes emerging insights into the multifaceted roles of PIEZO2 in cancer biology, summarize clinical correlations, highlight areas with concordant directionality (e.g., colorectal cancer, medulloblastoma) versus paradoxical findings (e.g., breast cancer across subtypes, gastric cancer by differentiation status), and provide a pragmatic framework for precision, context aware targeting. While PIEZO2 remains attractive for combination strategies (anti-angiogenesis, barrier modulation, dormancy escape, radio/chemo sensitization) and cancer pain interfaces, the field lacks truly PIEZO2 selective small molecule modulators. We propose feasible future priorities encompassing both pharmacologic and non-pharmacologic strategies to accelerate translational applications. Graphical Abstract