Targeting lipid scrambling potentiates ferroptosis and triggers tumor immune rejection.

Despite advances in understanding the metabolic mechanisms of ferroptosis, the molecular events following lipid peroxide accumulation on the plasma membrane (PM) remain unclear. Herein, we identify TMEM16F as a ferroptosis suppressor at the executional phase. TMEM16F-deficient cells display heightened sensitivity to ferroptosis. Mechanistically, TMEM16F-mediated phospholipids (PLs) scrambling orchestrates extensive remodeling of PM lipids, translocating PLs at the lesion sites to reduce membrane tension, therefore mitigating the membrane damage. Unexpectedly, failure of PL scrambling in TMEM16F-deficient cells leads to lytic cell death, exhibiting PM collapse and unleashing substantial danger-associated molecule patterns. TMEM16F-deficient tumors exhibit decelerated progression. Notably, lipid scrambling inhibition synergizes with PD-1 blockade to trigger robust tumor immune rejection. The antiparasitic drug ivermectin enhances the responsiveness to PD-1 blockade by suppressing TMEM16F. Our findings uncover TMEM16F-mediated lipid scrambling as an anti-ferroptosis regulator by relocating PLs on the PM during the final stages of ferroptosis. Targeting TMEM16F-mediated lipid scrambling presents a promising therapeutic strategy for cancer treatment.