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. The gene discussed is PIEZO2; the disease is medulloblastoma.