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

Abstract

The cancer-immune cycle conceptualized the mechanisms of driving T cell responses to tumors, but w as 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 antitumor immunological effects. Here 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, is reported. 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.