Ultrasound-responsive nanoplatforms for cancer immunotherapy: engineering spatiotemporal immune activation in the tumor microenvironment

Abstract

Immune checkpoint blockade has reshaped cancer therapy, but durable responses remain limited by insufficient antigen release, poor T-cell infiltration, immunosuppressive tumor microenvironments, and systemic immune-related toxicity. Ultrasound-responsive nanoplatforms provide a spatiotemporally controllable strategy to overcome these barriers by exploiting deep tissue penetration, focal activation, and repeatable external triggering. In this review, we summarize recent experimental advances in sonosensitizer-based and ultrasound-triggered nanoplatforms for cancer immunotherapy. These systems integrate sonodynamic immunogenic cell death, pyroptosis, ferroptosis, necroptosis, cGAS-STING activation, immune checkpoint blockade, mRNA delivery, gas therapy, and tumor microenvironment remodeling to convert immune-cold tumors into immune-responsive lesions. We further discuss cancer type-specific applications in hepatocellular carcinoma, pancreatic cancer, glioblastoma, triple-negative breast cancer, colorectal cancer, bladder cancer, and other solid tumors, emphasizing how ultrasound-responsive designs can be matched to distinct anatomical and immunological barriers. Finally, we highlight key translational challenges, including long-term biosafety, controllable immune activation, ultrasound parameter standardization, scalable manufacturing, and clinically compatible combination strategies. Ultrasound-responsive nanoplatforms are emerging not merely as drug carriers, but as programmable immune-engineering systems capable of coordinating when, where, and how antitumor immunity is activated within the tumor microenvironment.