Autophagic blockade potentiates anlotinib-mediated ferroptosis in anaplastic thyroid cancer.

Anlotinib-mediated angiogenic remodeling was delineated in various tumors. Meanwhile, we previously showed that anlotinib inhibited tumor angiogenesis in anaplastic thyroid cancer (ATC). However, the potential role of anlotinib on cell lethality in ATC remains an enigma. Herein, we found that anlotinib inhibited the viability, proliferation, and migration of KHM-5M, C643, and 8505C cells in a dose-dependently manner. Under anlotinib treatment, PANoptosis (pyroptosis, apoptosis, and necroptosis) markers were not changed; however, ferroptosis targets (transferrin, HO-1, FTH1, FTL, and GPX4) were significantly downregulated. ROS levels also increased in a concentration-dependent manner after anlotinib treatment in KHM-5M, C643, and 8505C cells. In addition, protective autophagy was activated in response to anlotinib, and autophagic blockade potentiated anlotinib-mediated ferroptosis and antitumor effects in vitro and in vivo. Our new discovery identified autophagy-ferroptosis signaling pathway which provides mechanistic insight into anlotinib-mediated cell death, and synergistic combination therapy may help develop new ATC treatment strategies.