Sensitization strategy for sonodynamic therapy

Sonodynamic therapy (SDT), a tumor treatment modality characterized by deep tissue penetration and high spatiotemporal precision, faces multiple challenges in clinical translation, including suboptimal sonosensitizer efficiency, suppression by the tumor microenvironment (TME), and insufficient induction of antitumor immune responses. This paper systematically reviews the multifaceted sensitization strategies of SDT, breaking away from traditional single-optimization approaches to establish a comprehensive synergistic enhancement framework spanning the entire chain involving "material design-microenvironment regulation-immune remodeling-synergistic therapy." In sonosensitizer engineering, current research emphasizes advanced design strategies-including defect engineering, heterostructure construction, and piezoelectric materials-to markedly enhance reactive oxygen species (ROS) generation through band structure modulation and mechano-electro-chemical coupling effects. To overcome the TME-associated constraints, a series of innovative strategies such as hypoxia alleviation, antioxidant depletion, metabolic reprogramming and bacteria-mediated targeted delivery have been developed to mitigate ROS scavenging and improve tumor selectivity. Furthermore, this review summarizes how SDT is integrated with multiple synergistic modalities such as chemodynamic therapy, phototherapy, immunotherapy, and ferroptosis/cuproptosis induction and systematically elucidates the underlying mechanisms and therapeutic potential of these combinations in triggering immunogenic cell death, reversing tumor immunosuppression, and ultimately enabling diagnostic-therapeutic integration. Despite persistent challenges in nanodelivery, controllable ROS generation, and clinical standardization, this review highlights that the development of multimodal, responsive, and biohybrid platforms is driving SDT toward a new paradigm of precise and intelligent cancer treatment. Collectively, these findings provide a systematic strategic blueprint with translational potential for treating deep-seated and drug-resistant solid tumors.