Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer

• 成果类型: Article
• 署名作者: Soula, Mariluz; Unlu, Gokhan; Welch, Rachel; Chudnovskiy, Aleksey; Uygur, Beste; Shah, Vyom; Alwaseem, Hanan; Bunk, Paul; Subramanyam, Vishvak; Yeh, Hsi-Wen; Khan, Artem; Heissel, Soren; Goodarzi, Hani; Victora, Gabriel D.; Beyaz, Semir; Birsoy, Kivanc
• 署名单位: Rockefeller University; Rockefeller University; Cold Spring Harbor Laboratory; Rockefeller University; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; University of California System; University of California San Francisco
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6690
• DOI: 10.1038/s41586-024-07787-1
• 发表日期: 2024-09-12
• 页码: 451-+
• 关键词: sphingolipid metabolism; cells; landscape; lipids; progression; expression; PATHWAY; reveal; GROWTH

摘要

Cancer cells frequently alter their lipids to grow and adapt to their environment(1-3). 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-gamma (IFN gamma) signalling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFN gamma receptor subunit 1 (IFNGR1), which mediates IFN gamma-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.