Glycosphingolipid synthesis mediates immune evasion in Kras-driven cancer

Cancer cells frequently alter their lipids to grow and adapt to their environment1–3. Despite the critical functions of lipid metabolism in membrane physiology, signaling, and energy production, how specific lipids contribute to tumorigenesis is 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 tumor growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer (NK) and CD8+ T cells partly via interferon gamma (IFNg) signaling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNg receptor subunit 1 (Ifngr1), mediating IFNg-induced growth arrest and proinflammatory signaling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumor immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion.

癌细胞常会通过重塑脂质谱以实现增殖与环境适应[1-3]。尽管脂质代谢在膜生理、信号传导与能量产生中发挥关键功能，但特定脂质如何参与肿瘤发生的完整机制仍未被完全阐明。本研究通过功能基因组学（functional genomics）与脂质组学（lipidomic）分析手段，鉴定出从头鞘脂合成（de novo sphingolipid synthesis）是肿瘤免疫逃逸的必需通路。令人意外的是，鞘脂合成对体外培养或免疫缺陷小鼠体内的癌细胞增殖并非必需，但在多种同基因肿瘤模型中却是肿瘤生长的必需条件。阻断癌细胞的鞘脂合成，可部分通过干扰素γ（interferon gamma, IFNγ）信号通路增强自然杀伤（natural killer, NK）细胞与CD8+ T细胞的抗增殖效应。机制层面，糖鞘脂（glycosphingolipids）的耗竭会上调癌细胞表面干扰素γ受体1亚基（IFNγ receptor subunit 1, Ifngr1）的表达水平，进而介导IFNγ诱导的生长阻滞与促炎信号转导。最后，糖鞘脂合成的药物抑制可与免疫检查点阻断（checkpoint blockade）疗法产生协同作用，强化抗肿瘤免疫应答。综上，本研究证实糖鞘脂是肿瘤免疫逃逸所必需的限制性代谢物。