Breaking barriers in immunotherapy: harnessing ultrasound for enhanced drug delivery and immune activation.

Immunotherapy represents a novel therapeutic modality based on the principle of modulating and augmenting the host immune response to combat disease, offering considerable therapeutic promise. However, its clinical implementation faces substantial barriers, such as delayed treatment responses and immune-mediated adverse effects. Ultrasound (US) has recently emerged as a highly promising adjuvant modality due to its non-invasiveness, established safety profile, and excellent spatiotemporal precision for deep-seated tissues. When synergistically combined with immunotherapeutic interventions, ultrasound not only potentiates treatment efficacy across diverse pathologies but also enables precise induction of immunogenic cell death for targeted immune activation. These multifaceted bioeffects collectively enhance therapeutic delivery while minimizing systemic toxicity. This comprehensive review elucidates the fundamental mechanisms by which US augments drug delivery to potentiate immunotherapeutic outcomes and highlights various ultrasound-responsive micro-/nanosystems. Furthermore, we discuss innovative combinatorial strategies integrating US with emerging paradigms such as sonomechanical, sonothermal, and sonodynamic therapies. Our critical analysis extends to disease-specific applications and recent advancements in US-assisted immunotherapy. Finally, we provide a forward-looking critical perspective on current challenges and future opportunities within this dynamic interdisciplinary field.