Harnessing the nonthermal effects of ultrasound for cancer treatment: From mechanisms to applications.

Ultrasound (US) was once predominantly used for diagnosis but not anymore. It has the capability to noninvasively deliver energy to the deep tissues and also enable spatiotemporal control. Unlike high-intensity focused ultrasound, which primarily ablates tumors through localized heat, nonthermal US converts acoustic energy into mechanical, cavitation, and physicochemical effects. The bioeffects that are induced under nonthermal US provide a mechanistic basis for cancer therapies. Here, we present a mechanism-guided framework that connects acoustic parameters and nonthermal bioeffects with therapeutic modalities. Nonthermal US-based cancer treatments are classified into six representative modalities: histotripsy, ultrasound-targeted microbubble destruction, sonogenetics, sonomechanical therapy (SMT), sonodynamic therapy (SDT), and sonopiezoelectric therapy (SPT). Through a review of recent advances in these modalities, we highlight emerging opportunities and future directions with a focus on standardizing acoustic dosimetry, biosafety assessment, and material optimization. These insights collectively establish a foundation for creating more reliable and clinically relevant nonthermal US-based therapies for precision oncology.