Electro‐Pyroptosis Immunotherapy of Cancer via Endoplasmic Reticulum‐Mitochondria Crosstalk Evoked by Ultrasound‐Activated Wireless Electrostimulation

ABSTRACT Effectively inducing endoplasmic reticulum (ER) stress to initiate cell pyroptosis is promising to elevate cancer immunotherapy, as it avoids immune escape of tumor cells and insufficient differentiation of immune cells. However, it remains a major challenge due to the lack of effective ways to induce ER stress. Herein, we reported the conceptually new electro‐pyroptosis immunotherapy (EPI‐therapy) of cancer via ER‐mitochondria crosstalk by wireless electrostimulation ( w ES), enabled by ultrasound‐activatable ER‐targeted piezoelectric nanoplatform of FAL&BaTiO 3 @AuNPs that capable of generating a voltage nearly 400 mV for localized w ES to induce ER stress to trigger reactive oxygen species (ROS) generation. The developed EPI‐therapy overperforms the existing drug/chemical‐stimulated ones; it disrupts mitochondrial homeostasis and immunosuppressive microenvironment and activates a long‐term immune memory effect, triggering pyroptosis and immunogenic cell death (ICD) effect to boost the immunogenicity, and hence efficiently inhibit primary tumor growth while resist tumor recrudesce and lung metastasis, promising for future immunotherapy of cancer.