Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer

Authors list

Mariluz Soula Gokhan Unlu Rachel Welch Aleksey Chudnovskiy Beste Uygur Vyom Shah Hanan Alwaseem Paul Bunk Vishvak Subramanyam Hsi-Wen Yeh Artem Khan Søren Heissel Hani Goodarzi Gabriel D Victora Semir Beyaz Kıvanç Birsoy
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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.

Journal details

Journal Nature
Volume 633
Issue number 8029
Pages 451-458
Available online
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Full text links

Publisher website (DOI) 10.1038/s41586-024-07787-1
Europe PubMed Central 39112706
Pubmed 39112706

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