Sonodynamic Therapy-Enhanced Immunotherapy for Triple-Negative Breast Cancer: Mechanistic Advances, Nanoplatform Strategies, and Clinical Prospects.

Abstract

Triple-negative breast cancer (TNBC) remains a major clinical challenge owing to its inherent resistance to treatment, immune-competent tumor microenvironment, and early metastasis. Sonodynamic therapy (SDT), which generates reactive oxygen species (ROS) using ultrasound, is a promising approach that combines localized apoptosis with systemic immune activation. In this review, we integrate biophysical principles, immunological targets, and nanoplatform design into diamond structures (discover, define, development, and deliver). We discuss the physical basis of SDT, including acoustic cavitation, sonoluminescence, and piezocatalysis; the non-apoptotic modalities of ferroptosis, pyroptosis, and mitophagy; and the activation of innate nucleic acid receptor-sensing pathways, such as the cGAS-STING. We are exploring nanotechnology, including oxygen-generating catalysts, GSH-depleting constructs, biomimetic and stimulus-responsive carriers for hypoxia and redox suppression, and theranostic probes. We assessed the durability of anti-tumor immunity induced by combination therapies. Finally, we outline the necessary preclinical toxicology and pharmacodynamics based on biomarkers to implement SDT as a programmable immuno-nanomedicine for aggressive TNBC.