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Updated: Sep 11, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Targeting lipid scrambling potentiates ferroptosis and triggers tumor immune rejection
Mengyun Yang1,2, Ze Yu3, Jieming Ping1,2
1Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China.
Abstract:
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.
Insights
TMEM16F suppresses ferroptosis by remodeling plasma membrane lipids. Inhibiting TMEM16F enhances ferroptosis and tumor immune rejection, offering a new cancer therapy strategy.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Ferroptosis is a regulated cell death pathway crucial in cancer, but its late-stage molecular mechanisms are not fully understood.
- Lipid peroxide accumulation on the plasma membrane (PM) is a hallmark of ferroptosis, yet subsequent events remain unclear.
Purpose of the Study:
- To identify molecular regulators of ferroptosis at the executional phase.
- To investigate the role of TMEM16F in ferroptosis and its therapeutic potential in cancer.
Main Methods:
- Utilized TMEM16F-deficient cell models and tumor xenografts.
- Performed lipidomic analysis and assessed cell death pathways.
- Investigated the synergistic effects of TMEM16F inhibition with PD-1 blockade in cancer models.
Main Results:
- TMEM16F deficiency sensitizes cells to ferroptosis and leads to lytic cell death.
- TMEM16F mediates phospholipid scrambling, remodeling the PM to mitigate ferroptosis-induced damage.
- TMEM16F inhibition synergizes with PD-1 blockade, enhancing tumor immune rejection and decelerating tumor progression.
- Ivermectin enhances PD-1 blockade responsiveness by suppressing TMEM16F.
Conclusions:
- TMEM16F acts as a ferroptosis suppressor by regulating plasma membrane lipid scrambling during ferroptosis.
- Targeting TMEM16F-mediated lipid scrambling presents a novel therapeutic strategy for cancer treatment, particularly in combination with immunotherapy.
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