Applying Ultrasound to Mechanically and Noninvasively Sensitize Prostate Tumors to TRAIL‐Mediated Apoptosis

Abstract Non‐surgical and safe prostate cancer (PCa) therapies are in demand. Soluble tumor necrosis factor (TNF‐α) related apoptosis inducing ligand (TRAIL), a cancer‐specific drug, shows preclinical efficacy but has a short circulation half‐life. This research has shown that physiological fluid shear stress activates mechanosensitive ion channels (MSCs), such as Piezo1, enhancing TRAIL‐mediated apoptosis in cancer cells. Herein, noninvasive, focal ultrasound (FUS) is implemented to augment the pro‐apoptotic effects of TRAIL. Using thermally safe FUS parameters, it is observed that TRAIL sensitivity increases with higher FUS pressure in PCa cells, mediated by Piezo1. This is confirmed by examining the effects of calcium chelation, MSC inhibitors, and PIEZO knockdown. In vivo, a multi‐dose study with 10 min FUS exposure shows that 0 and 4‐h intervals between TRAIL and FUS significantly reduce tumor burden, with an increase in apoptosis evident by enhanced cleaved‐caspase 3 expression. This mechanotherapy offers a clinically translatable approach by utilizing widely available FUS technology, applicable to treat additional cancer types.