Ultrasound‐Activated Hydrogen‐Bonded Organic Framework Synergistically Enhances Antitumor Immunity by Epigenetic Reprogramming and Pyroptosis Induction

ABSTRACT Pyroptosis, a pro‐inflammatory form of cell death, elicits robust antitumor immune responses. However, pyroptosis‐based cancer immunotherapy is hampered by the epigenetic silencing of gasdermin E (GSDME) through hypermethylation of the DFNA5 gene. To overcome this limitation, we engineered an innovative nanosystem by first synthesizing a reactive oxygen species (ROS)‐responsive decitabine prodrug (DTO), which was subsequently encapsulated within hydrogen‐bonded 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 DFNA5 and restore GSDME expression and (2) activating caspase‐3, thereby initiating the caspase‐3/GSDME‐mediated pyroptotic pathway. This apoptosis‐to‐pyroptosis switching mechanism significantly enhanced immunogenic cell death and potentiated antitumor immunity. In vivo studies demonstrated that US‐activated HDTO induced robust pyroptosis, remodeled the tumor microenvironment, and elicited superior antitumor immune responses, resulting in marked suppression of tumor growth and metastasis. Single‐cell RNA sequencing analysis confirmed that HDTO + US‐induced 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.