Ultrasound-activated Piezocatalytic nanomedicine for tumor microenvironment remodeling and immunotherapy.

The physical and immunosuppressive features of the tumor microenvironment limit drug delivery, immune-cell infiltration, and the response of many solid tumors to immunotherapy. Piezocatalytic nanomedicine uses ultrasound to activate piezoelectric nanomaterials, producing charge separation, local electrical effects, and reactive oxygen species within tumors. These effects can induce cellular stress and regulated tumor-cell death and, when associated with immunogenic cell death, promote the release or exposure of damage-associated molecular patterns that support dendritic-cell activation and subsequent T-cell responses. Beyond tumor-cell injury, emerging evidence suggests that piezocatalytic treatment may also influence several barriers within the tumor microenvironment, including stromal structure, intratumoral transport, tumor-associated macrophages, regulatory T cells, myeloid-derived suppressor cells, and effector T-cell infiltration and function. This review examines these processes from a tumor microenvironment-centered perspective and discusses how material design, piezocatalytic activation, immune responses, and barrier remodeling are connected. We also consider the rationale for combining piezocatalytic nanomedicine with immune checkpoint blockade and other treatments according to the biological barriers that remain after local treatment. Finally, we discuss major challenges for clinical translation, including material biodistribution and clearance, ultrasound dosimetry in deep tissues, spatial coordination of material delivery and acoustic exposure, and the need for more informative preclinical models. A barrier-oriented framework may help guide the design and evaluation of piezocatalytic platforms for cancer immunotherapy.