Recent advances in nanoparticles-based sonodynamic and immune checkpoint blockade synergistic therapy for pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) represents a major clinical challenge due to its dense fibrotic stroma, hypovascular characteristics, and immunosuppressive tumor microenvironment (TME), which collectively hinder effective drug delivery and contribute to recurrence and metastasis. The TME not only restricts therapeutic penetration but also compromises antitumor immune responses through multiple immunosuppressive mechanisms, thereby constituting a central obstacle in PDAC treatment. Nanoparticles (NPs)-mediated sonodynamic therapy (SDT) offers several advantages, including enhanced tissue penetration, improved biosafety profiles, and reactive oxygen species (ROS)-independent tumor-killing mechanisms. Nevertheless, the limitation to tumor inhibition instead of shrinkage and the incapability of eliminating metastatic tumors hinder the clinical potential for SDT. Fortunately, immune checkpoint blockade (ICB) can revive immunological function and induce a long-term immune memory against tumor rechallenges. Therefore, the synergistic combination of NP-based SDT with ICB presents a promising strategy for improving therapeutic outcomes in PDAC. This review provides an overview of the fundamental principles underlying ultrasonic cavitation, sonodynamic effects, sonosensitizer classification, and ICB mechanisms. This review highlighted the synergistic anti-tumor mechanisms and summarized the representative preclinical trials on SDT-assisted immunotherapy. Furthermore, this work explores the molecular basis of SDT-ICB synergy from the perspective of TME complexity. In addition, current nanomedicine engineering approaches aimed at overcoming stromal barriers in pancreatic tumors are critically evaluated. Finally, key challenges and future directions for the development of this combinatorial therapeutic strategy are discussed, offering novel perspectives on the application of biomaterials in advanced cancer therapy.