Integrating chemotherapy and sonodynamic therapy for lung cancer: a review

Chemotherapy remains a cornerstone of lung cancer treatment but is frequently limited by therapeutic resistance and systemic toxicities, creating a need for strategies that improve tumor localization without proportionally increasing systemic exposure. Sonodynamic therapy (SDT) and chemo-sonodynamic therapy (CSDT) are investigational approaches that use ultrasound-triggered reactive oxygen species (ROS) to injure tumor cells and, in CSDT, to potentiate drug activity. The available lung cancer-specific evidence comprises 20 primary studies spanning early chlorin e6 and sinoporphyrin sodium experiments, nanocarrier-based drug delivery, hypoxia modulation, resistance reversal, orthotopic pulmonary delivery, and recent SDT-immunotherapy platforms. However, it remains dominated by non-small-cell lung cancer, ectopic tumor models, short-term endpoints, and incompletely reported acoustic exposures; only one study used a small-cell lung cancer model, and clinical efficacy and safety in patients have not yet been established. In this review, we critically evaluate the mechanistic rationale and lung cancer-specific preclinical evidence, clearly separating it from evidence extrapolated from other tumor types. We also examine pulmonary acoustic barriers, realistic transthoracic and endoscopic delivery routes, ultrasound dosimetry, nanocarrier manufacturability and safety, and the emerging but still preclinical intersection with immune checkpoint blockade. This evidence-graded, delivery-oriented framework identifies the experiments needed before clinical translation can be justified.