Cancer cells frequently alter their lipids to grow and adapt to their environment^1,2,3. 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以生长和适应环境^1,2,3 。尽管脂质代谢在膜生理学、信号传导和能量产生中具有关键功能，但特定脂质如何促进肿瘤发生仍不完全清楚。在这里，我们利用功能基因组学和脂质组学方法，确定鞘脂从头合成是癌症免疫逃避的重要途径。令人惊奇的是，鞘脂的合成对于培养物或免疫缺陷小鼠中的癌细胞增殖来说是可有可无的，但在多种同基因模型中却是肿瘤生长所必需的。阻断癌细胞中鞘脂的产生可部分通过干扰素-γ (IFNγ) 信号传导增强自然杀伤细胞和 CD8 ⁺ T 细胞的抗增殖作用。从机制上讲，鞘糖脂的消耗会增加 IFNγ 受体亚基 1 (IFNGR1) 的表面水平，从而介导 IFNγ 诱导的生长停滞和促炎信号传导。最后，鞘糖脂合成的药理抑制与检查点阻断疗法协同作用，增强抗肿瘤免疫反应。总而言之，我们的工作确定了鞘糖脂是癌症免疫逃避所必需的和限制代谢物。