Vorapaxar enhanced mitochondria-associated ferroptosis primes cancer immunotherapy via targeting FOXO1/HMOX1 axis
Qian Zhou, Yuming Sun, Songtao Du, Yating Dian, Lei Yao, Hui Su, Ziyu Guo, Yu Meng, Yixiao Xiong, Zhili Deng, Xinwei Kuang, Xiaowei Liang, Hong Liu, Guangtong Deng, Xiang Chen, Furong Zeng
Abstract
Immunotherapy has revolutionized cancer treatment, yet challenges persist, such as resistance and lethal thromboembolism, necessitating dual-purpose strategies. Targeting ferroptosis emerges as a promising strategy to enhance immunotherapy efficacy, prompting our investigation of antiplatelet agents that simultaneously promote ferroptosis and mitigate thromboembolic risks. Through systematic screening of 20 Food and Drug Administration (FDA)-approved antiplatelet agents, we identify vorapaxar as a potent pro-ferroptotic drug. Mechanistically, vorapaxar binds forkhead box O1 (FOXO1), inhibits its phosphorylation at Ser256, and facilitates nuclear translocation to upregulate heme oxygenase 1 (HMOX1), promoting mitochondrial iron overload and mitochondria-associated ferroptosis. Vorapaxar enhances immunotherapy-induced tumor ferroptosis and antitumor immunity across diverse melanoma models, including B16F10 tumor-bearing mice, Braf/Pten-driven spontaneous melanoma mice, and peripheral blood mononuclear cell (PBMC)-humanized mice. Clinically, high FOXO1/HMOX1 co-expression correlates with improved immunotherapy response and progression-free survival. These findings position vorapaxar as a promising adjunct to immunotherapy, offering a dual benefit for cancer patients requiring both antithrombotic therapy and immunotherapy.