Ultrasound-induced immunogenic cell death in cancer: mechanisms, immune remodeling, and therapeutic opportunities

Therapeutic ultrasound is emerging as a spatially controllable strategy for converting local tumor destruction into systemic antitumor immunity. Beyond direct cytotoxicity, sonodynamic therapy, ultrasound-targeted microbubble or nanobubble destruction, low-intensity focused ultrasound, and histotripsy can induce immunogenic cell death (ICD) through reactive oxygen species generation, endoplasmic reticulum stress, mitochondrial damage, cGAS-STING activation, pyroptosis, ferroptosis, and necroptosis. These processes promote calreticulin exposure, ATP secretion, HMGB1 release, tumor antigen liberation, dendritic-cell maturation, and CD8 + T-cell priming, thereby remodeling immune-suppressive tumor microenvironments and sensitizing tumors to immunotherapy. Recent experimental studies further show that ultrasound-responsive nanoplatforms can integrate sonosensitizers, chemotherapeutics, immune checkpoint inhibitors, STING agonists, cytokine mRNA, miRNA, or siRNA to amplify ICD and overcome immune resistance. However, clinical translation remains limited by heterogeneous ultrasound parameters, inconsistent ICD validation, complex nanomaterial design, and insufficient biomarker-guided patient selection. This review summarizes recent advances in ultrasound-induced ICD, highlights the immune mechanisms connecting tumor cell death with adaptive immunity, and discusses rational combination strategies with PD-1/PD-L1 blockade, STING activation, chemotherapy, and gene-based immunotherapy. We propose that future sono-immunotherapy should shift from maximizing tumor killing toward exploiting ultrasound-induced immune responses to create new therapeutic opportunities.