Facilitated by reactive oxygen species (ROS)-involved therapies, tumor cells undergo immunogenic cell death (ICD) to stimulate long-term immunity response. However, it is hard to trigger abundant and large-scale ICD for satisfactory cancer immunotherapy. Herein, a multifunctional sonosensitizer that consists of Au single atoms and clusters anchored on TiO₂ nanosheets (named Au_S/C-TiO₂) is reported for augmented sonodynamic therapy (SDT) and glucose depletion, which ultimately induce robust ICD due to the improved ROS generation and strong endoplasmic reticulum (ER) stress. The synergy effect between Au cluster/single atom with TiO₂ nanosheets intensifies apoptosis and ICD pathways to inhibit 80% of tumor cells through in vivo analyses. Furthermore, immune cells in vivo analyses verify the effectiveness of Au_S/C-TiO₂ sonosensitizer towards the induction of antitumor immunity. This study thus reveals that simultaneous presence of ROS generation and strong ER stress can efficiently evoke a strong ICD-mediated immune response.