Ultrasound-Activatable Sonodynamic Amplifiers Reprogram Tryptophan Catabolism for Potentiating Remotely-Controlled Ferroptosis-Immunotherapy of Triple Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a highly invasive malignancy that responds poorly to current standard therapies. Sonodynamic therapy (SDT) can deliver both reactive oxygen species (ROS)-dependent tumor cytotoxicity and immunostimulatory benefits that holds significant promise for TNBC treatment, but its efficacy is blunted by the elevated Indoleamine 2,3-dioxygenase 1 (IDO1)-driven tryptophan (Trp) catabolism in TNBC, which strengthens antioxidant defenses while exacerbating the immunosuppressive tumor microenvironment. Here we develop an ultrasound-activatable sonodynamic amplifier (PMFN) that reprograms TNBC-intrinsic IDO1-dependent Trp catabolism to potentiate remotely controllable sonodynamic ferroptosis-immunotherapy. We first developed Fe(III)-coordinated tetraphenylporphyrin (FeTPP) as a ferrocatalytic sonosensitizer via molecular-dynamics-assisted virtual screening, which was co-formulated with the IDO1 inhibitor Navoximod (NLG919) into cRGD-modified liposomes for TNBC-targeted delivery. Upon ultrasonication, NLG919 blocks Trp-to-kynurenine (Kyn) conversion to suppress the Nrf2-GPX4 antioxidant axis and mitigate regulatory T cells (Tregs)-associated immunosuppression, while FeTPP amplifies ROS stress through a sonodynamic reaction to drive lipid peroxidation. These effects synergistically promoted immunogenic ferroptosis of TNBC cells and relieved immune suppression, thereby enhancing ferroptosis-immunotherapeutic efficacy. In mouse models, PMFN markedly inhibited primary TNBC growth and abrogated metastasis, providing an approach for advancing TNBC treatment in the clinic.