Abstract
Cancer cells frequently alter their lipids to grow and adapt to their environment1-3. Despite the critical functions of lipid metabolism in membrane physiology, signalling and energy production, how specific lipids contribute to tumorigenesis remains incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion. Synthesis of sphingolipids is surprisingly dispensable for cancer cell proliferation in culture or in immunodeficient mice but required for tumour growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer and CD8+T cells partly via interferon-γ (IFNγ) signalling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNγ receptor subunit 1 (IFNGR1), which mediates IFNγ-induced growth arrest and pro-inflammatory signalling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumour immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion.
癌细胞经常改变其脂质代谢以生长和适应环境。尽管脂质代谢在膜生理、信号传导和能量产生方面具有重要功能，但人们对特定脂质如何促进肿瘤发生的了解仍然不够全面。在这里，我们利用功能基因组学和脂质体组学方法，发现从头合成鞘脂是肿瘤免疫逃避的重要途径。令人惊讶的是，鞘脂的合成在培养或免疫缺陷小鼠中对癌细胞的增殖是不可或缺的，但在多种合成模型中对肿瘤的生长却是必需的。阻断癌细胞中鞘磷脂的生成，可部分通过干扰素-γ（IFNγ）信号增强自然杀伤细胞和CD8+ T细胞的抗增殖作用。从机制上讲，消耗糖磷脂会增加IFNγ受体亚基1（IFNGR1）的表面水平，而IFNGR1会介导IFNγ诱导的生长停滞和促炎信号。最后，药物抑制糖磷脂的合成可与检查点阻断疗法协同作用，增强抗肿瘤免疫反应。总之，我们的研究发现糖磷脂是癌症免疫逃避的必要和限制性代谢物。
参考文献
Soula M, Unlu G, Welch R, Chudnovskiy A, Uygur B, Shah V, Alwaseem H, Bunk P, Subramanyam V, Yeh HW, Khan A, Heissel S, Goodarzi H, Victora GD, Beyaz S, Birsoy K. Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer. Nature. 2024 Aug 7. doi: 10.1038/s41586-024-07787-1. Epub ahead of print. PMID: 39112706.
