Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer

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 and Kıvanç Birsoy ()
Additional contact information
Mariluz Soula: The Rockefeller University
Gokhan Unlu: The Rockefeller University
Rachel Welch: The Rockefeller University
Aleksey Chudnovskiy: The Rockefeller University
Beste Uygur: The Rockefeller University
Vyom Shah: Cold Spring Harbor
Hanan Alwaseem: The Rockefeller University
Paul Bunk: Cold Spring Harbor
Vishvak Subramanyam: University of California, San Francisco
Hsi-Wen Yeh: The Rockefeller University
Artem Khan: The Rockefeller University
Søren Heissel: The Rockefeller University
Hani Goodarzi: University of California, San Francisco
Gabriel D. Victora: The Rockefeller University
Semir Beyaz: Cold Spring Harbor
Kıvanç Birsoy: The Rockefeller University

Nature, 2024, vol. 633, issue 8029, 451-458

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07787-1

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