2026-04-17T03:10:22Zhttps://recercat.cat/oai/request

oai:recercat.cat:2072/4817232025-09-17T08:09:00Zcom_2072_98col_2072_378192

Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity Cuyàs, Elisabet Pedarra, Stefano Verdura, Sara Pardo-Cea, Miguel Ángel Espin Garcia, Roderic Serrano-Hervás, Eila Llop-Hernández, Àngela Teixidor, Eduard Bosch-Barrera, J López-Bonet, Eugeni Martin-Castillo, Begoña Lupu, Ruth Pujana, Miguel Angel Sardanyés, Josep Alarcón Cor, Tomás Menendez, Javier A. 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-X-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. 2024 Article Agencia Estatal de Investigación PID2019-104055GB-I00 Agencia Estatal de Investigación PID2022-141955OB-I00 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-01507 Agencia Estatal de Investigación CEX2020-001084-M Agencia Estatal de Investigación RTI2018.098322-B-I00 Agencia Estatal de Investigación PID2021-127896OB-I00 Agencia Estatal de Investigación RYC-2017-22243 Instituto de Salud Carlos III CP20/00003 Instituto de Salud Carlos III PI22/00297 Instituto de Salud Carlos III PI21/0136 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-00184 Cell Death Discovery ; Vol. 10 (September 2024), art. 417 open access Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. https://creativecommons.org/licenses/by/4.0/