2. Academic Validation
  3. ACSL4-mediated lipid rafts prevent membrane rupture and inhibit immunogenic cell death in melanoma

ACSL4-mediated lipid rafts prevent membrane rupture and inhibit immunogenic cell death in melanoma

  • Cell Death Dis. 2024 Sep 29;15(9):695. doi: 10.1038/s41419-024-07098-3.
Xi Zhao # 1 2,  Zenglu Zhao # 1 2,  Bingru Li 1 2,  Shuyu Huan 1 2,  Zixi Li 1 2,  Jianlan Xie 3,  Guoquan Liu 4 5 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
  • 2 Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Peking University, Beijing, China.
  • 3 Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • 4 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China. guoquanliu@bjmu.edu.cn.
  • 5 Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Peking University, Beijing, China. guoquanliu@bjmu.edu.cn.
  • 6 Department of Biomedical Engineering, Institute of Advanced Clinical Medicine, Peking University, Beijing, 100191, China. guoquanliu@bjmu.edu.cn.
  • # Contributed equally.
PMID: 39343834 DOI: 10.1038/s41419-024-07098-3
Abstract

Chemotherapy including platinum-based drugs are a possible strategy to enhance the immune response in advanced melanoma patients who are resistant to immune checkpoint blockade (ICB) therapy. However, the immune-boosting effects of these drugs are a subject of controversy, and their impact on the tumor microenvironment are poorly understood. In this study, we discovered that lipid peroxidation (LPO) promotes the formation of lipid rafts in the membrane, which mediated by Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) impairs the sensitivity of melanoma cells to platinum-based drugs. This reduction primarily occurs through the inhibition of immunogenic Ferroptosis and Pyroptosis by reducing cell membrane pore formation. By disrupting ACSL4-mediaged lipid rafts via the removal of membrane Cholesterol, we promoted immunogenic cell death, transformed the immunosuppressive environment, and improved the antitumor effectiveness of platinum-based drugs and immune response. This disruption also helped reverse the decrease in CD8+ T cells while maintaining their ability to secrete cytokines. Our results reveal that ACSL4-dependent LPO is a key regulator of lipid rafts formation and antitumor immunity, and that disrupting lipid rafts has the potential to enhance platinum-based drug-induced immunogenic Ferroptosis and Pyroptosis in melanoma. This novel strategy may augment the antitumor immunity of platinum-based therapy and further complement ICB therapy.

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