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However, pyroptosis\u2010based cancer immunotherapy is hampered by the epigenetic silencing of gasdermin E (GSDME) through hypermethylation of the\n                    <jats:italic>DFNA5<\/jats:italic>\n                    gene. To overcome this limitation, we engineered an innovative nanosystem by first synthesizing a reactive oxygen species (ROS)\u2010responsive decitabine prodrug (DTO), which was subsequently encapsulated within hydrogen\u2010bonded organic frameworks to form the HDTO nanoplatform. Upon ultrasound (US) activation, the HDTO nanoplatform exhibited potent ROS generation, enabling two complementary functions: (1) triggering decitabine release to demethylate\n                    <jats:italic>DFNA5<\/jats:italic>\n                    and restore GSDME expression and (2) activating caspase\u20103, thereby initiating the caspase\u20103\/GSDME\u2010mediated pyroptotic pathway. This apoptosis\u2010to\u2010pyroptosis switching mechanism significantly enhanced immunogenic cell death and potentiated antitumor immunity. In vivo studies demonstrated that US\u2010activated HDTO induced robust pyroptosis, remodeled the tumor microenvironment, and elicited superior antitumor immune responses, resulting in marked suppression of tumor growth and metastasis. Single\u2010cell RNA sequencing analysis confirmed that HDTO + US\u2010induced pyroptosis depleted nonimmune cells while expanding monocyte and neutrophil populations, demonstrating effective immunoreprogramming. This study establishes a novel therapeutic paradigm that synergistically integrates epigenetic modulation with pyroptosis induction to enhance the efficacy of cancer immunotherapy.\n                  <\/jats:p>","DOI":"10.1002\/adma.75356","type":"journal-article","created":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T10:57:41Z","timestamp":1792666661000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ultrasound\u2010Activated Hydrogen\u2010Bonded Organic Framework Synergistically Enhances Antitumor Immunity by Epigenetic Reprogramming and Pyroptosis Induction"],"prefix":"10.1002","author":[{"given":"Fan","family":"Zhuang","sequence":"first","affiliation":[{"name":"Department of Ultrasound Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Ultrasound 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