Year: 2026
Type: article
Abstract: Activation of conventional dendritic cells (cDCs) favors increased glycolysis-driven lactic fermentation, while oxidative phosphorylation (OXPHOS) links to tolerance. Here, selective targeting of the mitochondrial electron transport chain (ETC) in cDCs uncovers a critical role for OXPHOS in regulating their immunogenicity. Disruption of ETC complex III dampens adjuvant-triggered primary human and mouse cDC1 activation and their capability to prime T cells for anti-cancer immunity, while it has a milder effect on cDC2s. Mechanistically, complex III impairment in cDC1s leads to a dysregulated redox and metabolite balance, altering DNA methylation of PU.1 and activator-protein-1 (AP-1) binding regions. These epigenetic changes hinder the rapid induction of immediate-early stimulus-induced genes in cDC1s upon stimulation. The reduced immunogenic responsiveness of ETC-impaired cDC1s can be rescued by ectopic expression of alternative oxidase and phenocopied by Tet2 deficiency. Our findings reveal that electron flow through the ETC maintains a poised activation state in cDC1s, essential for effective anti-tumor immunity.
Source: Cell Metabolism
Authors: Ignacio Heras-Murillo, Diego Mañanes, Josep Calafell-Segura, Adrián Belinchón García, Clara Borràs-Eroles, Pablo Munné, Annalaura Mastrangelo, Sarai Martínez-Cano, Pablo Hernansanz-Agustín, María A. Zuriaga, José J. Fuster, Marten Szibor, Ignacio Melero, José Antonio Enríquez, Navdeep S. Chandel, Esteban Ballestar, Stefanie K. Wculek, David Sancho
Institutions: Spanish National Centre for Cardiovascular Research, Universidad Autónoma de Madrid, Josep Carreras Leukaemia Research Institute, Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, Inmunotek (Spain), Centro de Neurociencias Cajal, Centro de Investigación en Red en Enfermedades Cardiovasculares, Centro de Investigación Biomédica en Red, Tampere University, Jena University Hospital, University of Tampere, Center for Sepsis Control and Care, University of Oxford, Centro de Investigación Médica Aplicada, Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable, Northwestern University, Chan Zuckerberg Biohub Chicago, East China Normal University
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $10,400
Funders: Institute for Research in Biomedicine, Fundació la Marató de TV3, Worldwide Cancer Research, Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable, Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades, Centres de Recerca de Catalunya, European Commission, Fundación Científica Asociación Española Contra el Cáncer, Generalitat de Catalunya, Ministerio de Ciencia e Innovación, Centro Nacional de Investigaciones Cardiovasculares, Consejería de Educación, Juventud y Deporte, Comunidad de Madrid, Fundación Fero, Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona, National Institutes of Health, European Research Council, Instituto de Salud Carlos III, Agencia Estatal de Investigación, National Cancer Institute
Awards: G1057098037, G1255325603, G1475301827, G1568717892, G1715104315, G1848349749, G2110111306, G3336564084, G3480869486, G3773137417, G4370694050, G4748589373, G4758880905, G5178665745, G5352889928, G5503124315, G5885781436, G5953118182, G6848022923, G6959332573, G7084143925, G7300085115, G7317625304, G7731791180, G798868971, G8656166595, Mitochondrial Metabolism and Cancer, G926782147
OpenAlex ID: W7154497919