State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Peking University, Beijing, China.
Cell Death Dis. 2024 Sep 29;15(9):695. doi: 10.1038/s41419-024-07098-3.
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.
化疗包括铂类药物在内，可能是增强对免疫检查点阻断（ICB）治疗耐药的晚期黑色素瘤患者免疫反应的一种策略。然而，这些药物的免疫增强作用存在争议，其对肿瘤微环境的影响也知之甚少。在这项研究中，我们发现脂质过氧化（LPO）促进膜中脂筏的形成，脂筏通过酰基辅酶 A 合成酶长链家族成员 4（ACSL4）介导，从而降低黑色素瘤细胞对铂类药物的敏感性。这种减少主要是通过抑制免疫原性铁死亡和焦亡来实现的，而抑制免疫原性铁死亡和焦亡是通过减少细胞膜孔形成来实现的。通过去除膜胆固醇破坏 ACSL4 介导的脂筏，我们促进了免疫原性细胞死亡，改变了免疫抑制环境，并提高了铂类药物和免疫反应的抗肿瘤效果。这种破坏还有助于逆转 CD8 T 细胞的减少，同时保持其分泌细胞因子的能力。我们的结果表明，ACSL4 依赖性 LPO 是脂筏形成和抗肿瘤免疫的关键调节剂，破坏脂筏有可能增强铂类药物诱导的黑色素瘤免疫原性铁死亡和焦亡。这种新策略可能增强铂类治疗的抗肿瘤免疫，并进一步补充 ICB 治疗。
