Breaking Apoptosis‐Induced Immune Silence: Ultrasound‐Activated Nano‐Oncolytic Therapy Reinvigorates Antitumor Immunity

Abstract Conventional tumor therapies typically depend on the apoptotic pathway, which often leads to inadequate immunogenicity. This limitation underscores the urgent need for innovative treatments that enhance immunogenicity. In this study, an ultrasound (US)‐activated nano‐oncolytic system (designated as cRGD‐Lip@PFP), is presented and consists of nanoliposomes (Lip) modified with the cRGD peptide for targeted tumor delivery. This system features a perfluoropentane (PFP) core that undergoes US‐triggered acoustomechanical effects, enabling controlled expansion from nanoscale to microscale, ultimately leading to rupture and the generation of cavitation effects. Intracellular cavitation further induces necroptosis‐like oncolytic cell death. The efficacy of various treatments in stimulating immune responses is systematically compared and it is demonstrated that the nano‐oncolytic system effectively enhances the release of damage‐associated molecular patterns (DAMPs). Additionally, the release of DNA fragments activates the cGAS‐STING pathway, resulting in an amplified immune response. Furthermore, this nano‐oncolytic system alleviates the hypoxic tumor microenvironment and counteracts immunosuppression. Compared to traditional apoptosis, the necroptosis‐like oncolytic cell death induced by this strategy exhibits enhanced immunogenicity. This approach presents an innovative paradigm for tumor immunotherapy based on acoustomechanical effects, offering a promising alternative to tackle the issue of insufficient immunogenicity often associated with conventional apoptosis therapies.