Piezoelectric‐Triggered Ferroptosis for Cancer Therapy via Cascade‐Enhanced Immune Response

A piezoelectric BaTiO₃-based ferroptosis inducer (BTO@Fe) generates significant reactive oxygen species (ROS) and depletes glutathione (GSH) through piezo-catalytic reactions. This process triggers immunogenic ferroptosis and enhances immune responses via the ROS/p53/SLC7A11/GSH/GPX4 and IFNγ/SLC7A11/GSH/GPX4 pathways under ultrasound (US). This study emphasizes the potential of leveraging the interactions between the piezoelectric effect and immune cells to enhance antitumor efficacy.

Abstract

Eliciting ferroptotic cell death in tumors has enhanced prospects for cancer therapy because of its proinflammatory properties, which enable damage-associated molecular pattern (DAMP) release and immune response activation. However, the immunogenicity of ferroptosis and how to controllably activate the self-enhanced antitumor immune response by cellular ferroptosis require further investigation. In this study, a piezoelectric BaTiO₃-based ferroptosis inducer (BTO@Fe) is synthesized for effective cancer immunotherapy. BTO@Fe induces moderate ferroptosis by introducing excess iron and catalyzing the Fenton reaction. When subjected to ultrasound (US) irradiation, the piezoelectrically excited electrons and holes are separated, further catalyzing reactive oxygen species (ROS) generation and glutathione (GSH) consumption and consequently causing intensified ferroptosis and immunogenic cell death (ICD). Moreover, activated CD8⁺ T cells respond to immune signals by releasing interferon gamma (IFNγ), which sensitizes tumor cells to ferroptosis in an intrinsic mechanism of ferroptosis initiation. The robust ferroptosis originating from exogenous piezocatalytic reactions and the endogenous immune responses demonstrates satisfactory in vitro and in vivo antitumor effects. This work suggests that doping-engineered piezoelectric materials with augmented catalytic activity are promising countermeasures for restoring immunogenicity in ferroptotic cells.