Nanosensitizer-enabled sonodynamic therapy (SDT) represents an appealing anti-tumor modality to induce apoptotic cancer-cell death by generating highly toxic reactive oxygen species (ROS). However, it suffers from discounted therapeutic efficacy due to the apoptosis-resistant mechanism of cancer cells. Inspired by the synergistic anti-tumor effect of ferroptosis and apoptosis, in this work, we have constructed a nanosonosensitizer (PpIX)-based liposomal nanosystem, which simultaneously encapsulated clinically approved iron supplement ferumoxytol, for inducing dual ferroptosis/apoptosis pathways by SDT-based oxidative ferrotherapy. The ferumoxytol as a ferroptosis initiator is utilized to deliver excessive iron into cancer cells, which achieves tumor metabolic rewiring and renders cancer cells extremely susceptible to SDT-induced cell apoptosis. Meanwhile, SDT enables the modulation of critical regulatory ferroptosis checkpoints through the process of ferritinophagy so as to improve ferroptosis sensitivity, thus achieving synergistic tumor suppression. The potential benefits of triggering ferroptosis-like cell death in the context of sonodynamic cancer treatment were substantially evidenced by augmented therapeutic efficacy both in vitro and in vivo, suggesting that such an efficient SDT-based ferroptosis-targeting strategy is highly promising to be an innovative tumor-treatment approach. (c) 2021 Elsevier Ltd. All rights reserved.