Abstract
Small-molecule drugs remain the mainstay of cancer therapy but are frequently compromised by poor tumor selectivity and dose-limiting systemic toxicity. Prodrug strategies have therefore been widely developed to improve therapeutic indices; however, conventional prodrugs that rely on endogenous biological stimuli often suffer from interpatient heterogeneity and unintended off-target activation. In this context, ultrasound (US) has emerged as a highly attractive exogenous trigger for on-demand prodrug activation owing to its excellent safety profile, deep tissue penetration, and precise spatiotemporal controllability. In this review, we provide a comprehensive and systematic overview of US-activated prodrugs for cancer therapy. We first summarize the fundamental physical principles of US and delineate four major US-induced effectsmechanical, cavitation, thermal, and chemicalhighlighting how each effect can induce specific chemical bond cleavage and drug release. Particular emphasis is placed on the rapidly advancing field of sonochemistry, especially sonosensitizer-mediated electron transfer and reactive oxygen species/radical generation, which enables highly efficient and controllable chemical activation of prodrugs under clinically relevant US conditions. By critically comparing activation mechanisms, chemical design strategies, and representative prodrug systems, this review clarifies the unique advantages and limitations of different US-responsive approaches. Importantly, we highlight recent advances that demonstrate the superiority of sonochemical activation in achieving precise, deep-tissue, and minimally invasive drug activation. Collectively, this work aims to provide conceptual and practical guidance for the rational design of next-generation US-activated prodrugs and to accelerate their translation toward safer and more effective precision cancer therapies.