Simultaneous activation of pyroptosis and cGAS-STING pathway with iridium(III) thiophene complexes for enhanced oral squamous cell carcinoma sono-immunotherapy

Sonodynamic therapy (SDT) has shown promise for treating oral squamous cell carcinoma (OSCC) due to its superior tissue penetration, excellent controllability, and promising immunomodulatory ability. However, its therapeutic efficacy is critically dependent on the sonodynamic performance of the sonosensitizers and is further influenced by the immunosuppressive tumor microenvironment. Developing efficient sonosensitizers and exploring rational combination strategies remain appealing tasks for improving OSCC management. Herein, a novel sonosensitizer, Ir5 , was synthesized through a thiophene modification and methyl optimization strategy based on an iridium(III) complex. Ir5 efficiently generates Type I and Type II reactive oxygen species (ROS) upon ultrasound (US) irradiation, exerting potent antitumor efficacy under both normoxia and hypoxia. Besides inducing pyroptosis for direct tumor ablation and triggering robust immunogenic cell death (ICD), Ir5 -SDT concurrently activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. As Ir5 -SDT adaptively increases the expression of programmed death ligand 1 (PD-L1), its combination with PD-L1 inhibitor effectively inhibits tumor growth and triggers robust tumoricidal immunity in vivo . Collectively, this study presents a rationally designed sonosensitizer with enhanced sonodynamic efficacy and demonstrates a synergistic sono-immunotherapeutic strategy that potentiates antitumor immunity via ICD, cGAS-STING activation, and PD-L1 blockade, offering a promising translational avenue for the treatment of OSCC.