TMEM87A loss enhances ferroptosis and potentiates PD1 blockade in murine tumors
TMEM87A was identified as a mediator of ferroptosis resistance through buffering Golgi pH. In murine tumor models, TMEM87A ablation suppressed tumor progression and potentiated PD1 blockade therapy.
TMEM87A is identified as a mediator of ferroptosis resistance through buffering Golgi pH, and 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, while tumoral TMEM87A expression negatively correlates with immunotherapy response and treatment outcome.
Ferroptosis inducer triggers rapid oxidation of Golgi membrane lipids in the early phase of ferroptosis, resulting in disruption of Golgi pH. Depletion of TMEM87A leads to Golgi overacidification, which impairs FSP1-mediated reduction of coenzyme Q.
The study states that lipid peroxidation accumulated on Golgi membrane causes the elevation of Golgi pH, which in turn protects tumor cells from ferroptosis execution. Golgi-localized TMEM87A can regulate ferroptosis by buffering Golgi pH.
In vivo, TMEM87A loss promotes tumoral ferroptosis, potentiates antitumor T cell responses and synergizes with ICB therapy. The study concludes that TMEM87A functions as a suppressor of tumoral ferroptosis by maintaining Golgi pH homeostasis and that targeting TMEM87A is potent to augment cancer immunotherapy.