Sonodynamic Therapy Induces Pyroptosis and Recruits CAR-NK Cells to Enhance the Treatment of Oral Squamous Cell Carcinoma

<b>Background:</b> Immunotherapy strategies have demonstrated promising efficacy in treating various cancers. However, cancer cells often evade immune surveillance by reducing their immunogenicity, which limits immune cell infiltration into the tumor microenvironment. Pyroptosis, a proinflammatory form of programmed cell death, is characterized by the formation of plasma membrane pores that lead to the release of intracellular contents and stimulate a robust immune response. <b>Results:</b> To exploit this mechanism, we developed hematoporphyrin monomethyl ether (HMME)-loaded nanoliposomes capable of efficiently accumulating at the tumor site. Upon ultrasound irradiation, these nanomedicines generate reactive oxygen species (ROS) that activate Caspase-3, which cleaves Gasdermin E (GSDME) and induces tumor cell pyroptosis. Notably, this sonodynamic therapy (SDT) based on nanosonosensitizers enhanced the targeted enrichment of chimeric antigen receptor (CAR)-engineered natural killer (NK) cells at the ultrasound-irradiated tumor site, significantly improved the tumor immune response, and effectively inhibited the growth and proliferation of oral squamous cell carcinoma (OSCC) cells both in vivo and in vitro. <b>Conclusions:</b> Given that NK cell immunotherapy has an excellent safety profile with minimal risks of cytokine release syndrome and neurotoxicity, this approach holds promise as an adjunct to various NK cell-based immunotherapies through SDT-induced pyroptosis.