Nanomaterials Enable Spatiotemporally Controlled Ultrasound-Triggered Pyroptosis for Cancer Immunotherapy.

Abstract

Pyroptosis, a highly inflammatory form of programmed cell death (PCD), holds exceptional promise for activating antitumor immunity. However, achieving precise and tumor-selective pyroptosis induction while preserving normal tissue integrity remains a major translational hurdle. Ultrasound has emerged as an ideal exogenous stimulus for this purpose, owing to its noninvasiveness, deep tissue penetration, and precise spatiotemporal control. Through integration with tailored nanomaterials, ultrasound energy can be specifically converted into localized biochemical signals at the tumor site, thereby triggering pyroptosis that potently stimulates antitumor immunity. This review systematically elucidates how rational nanomaterial design enables ultrasound-triggered pyroptosis (sonopyroptosis) through distinct mechanisms, including sonodynamic, sonopiezocatalytic, enzyme-mimetic, and multimodal synergistic pathways. It further delineates the ensuing immune cascade, from innate immune activation and adaptive T cell responses to the remodeling of the immunosuppressive tumor microenvironment (TME), and evaluates the synergistic potential of this approach with emerging immunotherapies such as immune checkpoint blockade (ICB) and cGAS-STING pathway activation. Finally, key challenges in clinical translation are outlined, and future perspectives are proposed to accelerate the development of nanomaterial-mediated ultrasound-triggered pyroptosis for cancer immunotherapy.