2. Academic Validation
  3. Targeting lipid scrambling potentiates ferroptosis and triggers tumor immune rejection

Targeting lipid scrambling potentiates ferroptosis and triggers tumor immune rejection

  • Sci Adv. 2025 Aug 15;11(33):eadx6587. doi: 10.1126/sciadv.adx6587.
Mengyun Yang 1 2,  Ze Yu 3,  Jieming Ping 1 2,  Yuanchun Duan 2,  Jianlong Tang 1 2,  Weixiang Liu 1 2,  Qing He 1,  Yongfeng Lai 1,  Sin Man Lam 4 5,  Hesen Tang 6,  Zhengjie Liu 7,  Weimin Wang 1,  Min Zhu 8,  Wei Hu 9,  Yunyun Han 10,  Guanghou Shui 4 5,  Jiqing Hao 11,  Zheng Liu 3,  Ning Wu 1 2 3 12
Affiliations

Affiliations

  • 1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China.
  • 2 The First Affiliated Hospital of Anhui Medical University and Institute of Clinical Immunology, Anhui Medical University, Hefei 230032, China.
  • 3 Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, China.
  • 4 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
  • 5 University of Chinese Academy of Sciences, Beijing 100101, China.
  • 6 School of Materials Science and Engineering, Key Laboratory of Structure and Functional Regulation of Hybrid Materials of Ministry of Education, Anhui University, Hefei, Anhui 230601, China.
  • 7 Institute of Physical Science and Information Technology, Anhui University, Hefei 230601, China.
  • 8 Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 9 Department of Clinical Pharmacology, the Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
  • 10 Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China.
  • 11 Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 12 Cell Architecture Research Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
PMID: 40815641 DOI: 10.1126/sciadv.adx6587
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.

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