Lymphocyte‐Mimicking Sonosensitizers Boost Cancer Immunotherapy via Sequential Ultrasound Activation

Abstract Effective initiation of the cancer‐immunity cycle is the core challenge of tumor immunotherapy, which relies on the coordinated antigen release and immunostimulation. To address this issue, this work introduced a novel lymphocyte‐mimicking sonosensitizer using Mn‐doped hollow Prussian blue nanoparticle (Mn‐HP) for cancer sonodynamic therapy (SDT) to efficiently evoke anticancer immunity. The prepared Mn‐HP have unique architecture to amplify ultrasonic cavitation effects, boosting spatially controlled reactive oxygen species (ROS) production. Through the effective combination of the Mn‐HP and lymphocytes, the Lymphocyte‐mimicking sonosensitizer (Lymphocytes‐Mn‐HP, LM) with the “Homing effect” is constructed. The sequenced dual‐ultrasound strategy employs high‐power ultrasound (2.0 W cm −2 ) stimulation (excessive ROS) for tumor antigen release and low‐power ultrasound (0.5 W cm −2 ) stimulation (moderate ROS) for lymph node to active immune cells, enabling precise spatial‐temporal controlled ROS generation while preserving immune function. Both in vitro and in vivo studies demonstrated significant tumor suppression through initiating the cancer‐immunity cycle, offering a transformative paradigm for SDT‐immunotherapy integration.