Oxygen/sulfate radicals-generating CaS2O8 nanosonosensitizers induce PANoptosis and calcium overload for enhanced peritoneal metastasis immunotherapy

Peritoneal metastasis (PM) is typically intractable by immunotherapy due to an immunosuppressive microenvironment and the peritoneal-plasma barrier. Sonodynamic therapy (SDT) presents unique advantages of noninvasive in situ treatment and the potential for antitumor immune activation. Building upon SDT technology, the study reports on a novel biodegradable sonosensitizer, CaS₂O₈, characterized by a narrow bandgap, abundant oxygen vacancies and a rapid ultrasound (US) response for abdominal SDT. Such sonosensitizer only produces lethal reactive oxygen species (ROS) after US irradiation, which is nontoxic in a physiological environment. After US irradiation, CaS₂O₈ yields a large amount of sulfate radical (SO₄⁻), as well as sonodynamic related ROS (OH, and ¹O₂), which exerts a synergistic effect with Ca²⁺ overload to induce Z-conformation nucleic acid by augmenting oxidative damage. As a result, the PANoptosis is initiated through the ZBP1/RIPK3 pathway in tumor cells. This inflammatory cell death leads to a multi-faceted release of tumor cell contents which serve as an in situ tumor antigen to induce a robust antitumor immune response. Notably, the precision sono-immunotherapy enhances the infiltration of T cells into tumors by transforming an immunosuppressive phenotype into an immunostimulatory one. Therefore, targeting PANoptosis by CaS₂O₈-induced SDT can provide an alternative or additional clinical treatment and prolonged survival outcome for patients with PM.