Immunogenic PANoptosis-initiated Cancer Sono-Immune Reediting Nanotherapy by Iteratively Boosting Cancer Immunity Cycle.

The cancer-immune cycle conceptualized the mechanisms of driving T cell responses to tumors, but was limited by immunological ignorance elicited by tumor inherent immunoediting, which failed to initiate and maintain adaptive immunity. Targeting specific vulnerabilities of cell death patterns may provide unique opportunities to boost T cell anti-tumor immunological effects. Here we report an ultrasound nanomedicine-triggered tumor immuno-reediting therapeutic strategy using nano/genetically engineered extracellular vesicles, which can induce tumor highly immunogenic PANoptosis and iteratively start-up the energization of cancer innate immunity cycle by repeatedly liberating damage-associated molecular patterns, thereby priming sufficient antigen-specific T cells and shaping protective immune response through activating cGAS-STING signaling pathways. Aided by immune checkpoint blockade, the reprogramming of immune microenvironment further facilitated a prompt bridging of innate and adaptive immunity, and remarkably suppressed metastatic and rechallenged tumor growth. Thus, targeting PANoptotic cell death provides a catcher against immune escape and a positive-feedback immune activation gateway for overcoming immune resistance to intractable cancers. This article is protected by copyright. All rights reserved.