TMEM87A suppresses ferroptosis and increases cancer immunotherapy resistance by maintaining the Golgi apparatus pH homeostasis

Most membrane-bound organelles have been linked to the initiation and execution of ferroptosis. However, the role of the Golgi apparatus and its resident proteins in ferroptosis remain elusive. Here we show that ferroptosis inducer triggers rapid oxidation of Golgi membrane lipids in the early phase of ferroptosis, resulting in disruption of Golgi pH. The Golgi-localized transmembrane protein TMEM87A is identified to mediate ferroptosis resistance through buffering Golgi pH. Depletion of TMEM87A leads to Golgi overacidification, which impairs FSP1-mediated reduction of coenzyme Q. In vivo, TMEM87A ablation suppresses the progression of multiple murine tumors including melanoma, colorectal cancer and liver cancer. TMEM87A ablation also enhances antitumor T cell responses and potentiates PD1 blockade therapy. Clinically, tumoral TMEM87A expression negatively correlates with immunotherapy response and treatment outcome. Our study reveals that TMEM87A functions as a suppressor of tumoral ferroptosis by maintaining Golgi pH homeostasis and targeting TMEM87A is potent to augment cancer immunotherapy.