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s41420-024-02184-z.pdf (5.02 MB)

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2024-09-30

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cc by (c) Cuyàs, Elisabet et al, 2024
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/215821

Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity

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https://doi.org/10.1038/s41420-024-02184-z

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Fatty acid synthase (FASN)-catalyzed endogenous lipogenesis is a hallmark of cancer metabolism. However, whether FASN is an intrinsic mechanism of tumor cell defense against T cell immunity remains unexplored. To test this hypothesis, here we combined bioinformatic analysis of the FASN-related immune cell landscape, real-time assessment of cell-based immunotherapy efficacy in CRISPR/Cas9-based FASN gene knockout (FASN KO) cell models, and mathematical and mechanistic evaluation of FASN-driven immunoresistance. FASN expression negatively correlates with infiltrating immune cells associated with cancer suppression, cytolytic activity signatures, and HLA-I expression. Cancer cells engineered to carry a loss-of-function mutation in FASN exhibit an enhanced cytolytic response and an accelerated extinction kinetics upon interaction with cytokine-activated T cells. Depletion of FASN results in reduced carrying capacity, accompanied by the suppression of mitochondrial OXPHOS and strong downregulation of electron transport chain complexes. Targeted FASN depletion primes cancer cells for mitochondrial apoptosis as it synergizes with BCL-2/BCL-XL-targeting BH3 mimetics to render cancer cells more susceptible to T-cell-mediated killing. FASN depletion prevents adaptive induction of PD-L1 in response to interferon-gamma and reduces constitutive overexpression of PD-L1 by abolishing PD-L1 post-translational palmitoylation. FASN is a novel tumor cell-intrinsic metabolic checkpoint that restricts T cell immunity and may be exploited to improve the efficacy of T cell-based immunotherapy.

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Àcids grassos, Càncer

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Fatty acids, Cancer

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Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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CUYÀS, Elisabet, PEDARRA, Stefano, VERDURA, Sara, PUJANA GENESTAR, M. ángel, ESPÍN GARCÍA, Roderic, SERRANO HERVÁS, Eila, LLOP HERNÁNDEZ, Àngela, TEIXIDOR, Eduard, BOSCH BARRERA, Joaquim, LÓPEZ BONET, Eugeni, MARTÍN CASTILLO, Begoña, LUPU, Ruth, PUJANA GENESTAR, M. ángel, SARDANYÈS, Josep, ALARCÓN, Tomás, MENÉNDEZ, Javier a.. Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity. _Cell Death Discovery_. 2024. Vol. 10, núm. 1. [consulta: 21 de gener de 2026]. ISSN: 2058-7716. [Disponible a: https://hdl.handle.net/2445/215821]

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