1T-phase niobium telluride (NbTe2) nanosheets are becoming increasingly important in emerging fields, such as spintronics, sensors and magneto-optoelectronics, due to their excellent physical and chemical properties. However, exploration on their biomedical applications are limited. Herein, ultrathin 1T-phase NbTe2 single-crystalline nanosheets with excellent photothermal performance, high drug-loading rate, near-infrared (NIR) light/acidic pH-triggered drug release, and low toxicity were developed for potentiated photothermal therapy. Importantly, they showed excellent biocompatibility in vivo and in vitro. NbTe2 nanosheets loaded with integrated stress response inhibitors (ISRIB) could achieve chemo-photothermal therapy of tumors through the ATF4-ASNS signaling axis. Ultrathin 1T-phase NbTe2 single-crystalline nanosheets with unique photothermal properties, drug loading rate and safety provide dramatic possibilities in biomedical applications, such as tissue imaging, photothermal therapeutics and pharmaceutics.