Ultrasound-responsive nanoparticles: Modulating the tumor microenvironment to advance cancer immunotherapy

<h2>Summary</h2> Cancer immunotherapy is a proven strategy against solid tumors, but its efficacy is often hindered by the immunosuppressive tumor microenvironment (TME) and immune-related side effects. Ultrasound-responsive nanoparticles (URNs) offer a precise strategy to activate immunomodulators at targeted sites, enhancing efficacy while reducing systemic toxicity. Upon ultrasound exposure, URNs modulate the TME through controlled release of therapeutics, induction of immunogenic cell death, sonoporation, improved vascular permeability, extracellular matrix (ECM) disruption, and overcoming intracellular barriers. These mechanisms strengthen the interplay between innate and adaptive immunity, thereby amplifying the cancer-immunity cycle. This review highlights unique advantages of URNs in TME remodeling and their applications in improving immune checkpoint blockade, cancer vaccines, T cell therapies, cytokine delivery, and site-specific innate immune activation. It also discusses synergistic opportunities with other complementary strategies, such as oxygenation, metabolic reprogramming, ECM degradation, alternative cell death pathways, and phototherapy, offering guidance for rational URN design for clinical cancer immunotherapy.