Mitochondria keep immune cells “ready to respond”
Scientist at the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) and the Institute for Research in Biomedicine (IRB Barcelona) uncover a key metabolic mechanism governing immune cell readiness
Researchers at the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) show that active mitochondria maintain dendritic cells, the immune system’s sentinels, in a “ready-to-respond” state, linking cellular metabolism to gene regulation and T-cell activation.
The findings, published in Cell Metabolism, open new avenues to improve vaccines and cancer immunotherapy.
The study was led by David Sancho at CNIC and Stefanie K. Wculek at the Institute for Research in Biomedicine (IRB Barcelona), with key contributions from Ignacio Heras Murillo as first author at CNIC.
Dendritic cells play a central role in immunity: they detect threats and activate T cells to fight infections and tumors. Understanding how these cells are regulated is crucial to both enhance immune responses and counteract their dysfunction in diseases such as cancer.
The study reveals that a specific mitochondrial process, the flow of electrons through the respiratory chain, is essential to keep these cells primed. This challenges the long-standing view that mitochondria play only a minor role during dendritic cell activation.
“Our findings show that mitochondria do much more than produce energy, they keep dendritic cells in a ‘ready’ state, allowing them to respond rapidly to threats such as tumors,” explains David Sancho.
Focusing on a specialized subset known as cDC1, which excels at activating tumor-killing T cells, the researchers used genetically modified mouse models and human dendritic cells to dissect mitochondrial function. Surprisingly, they found that immune readiness does not depend primarily on energy production (ATP), but on maintaining electron flow through the mitochondrial chain.
“What is remarkable is that this process is not about energy production, but about preserving the cell’s internal balance, which directly shapes how genes respond to danger signals,” says Ignacio Heras Murillo.
This electron flow preserves the cell’s internal chemical balance, including redox state and metabolite levels. In collaboration with experts in epigenetics, the team showed that disrupting this balance alters DNA methylation patterns at key regulatory regions, molecular switches that enable rapid gene activation. The enzyme TET2 emerged as a critical player, and its activation, for example with vitamin C, enhanced dendritic cell function in experimental models.
Functionally, impaired electron flow had major consequences: dendritic cells showed reduced activation, diminished migration to lymph nodes, and a weakened ability to stimulate T cells. As a result, anti-tumor immune responses were compromised.
“These results highlight metabolism as a key regulator of immune function and suggest new strategies to boost dendritic cell activity in cancer and other diseases,” adds Stefanie K. Wculek.
Importantly, the researchers demonstrated that restoring electron flow could rescue these defects. By introducing an alternative enzyme (AOX), they reinstated mitochondrial function without increasing energy production, recovering the cells’ ability to activate T cells and control tumor growth in mice.
These findings identify a previously unrecognized “electron flow checkpoint” that governs immune cell readiness. Targeting this metabolic pathway could enhance dendritic cell-based therapies, particularly in cancers where immune activation is impaired.
The study highlights metabolism as a powerful lever to fine-tune immune responses and paves the way for new strategies in immunotherapy and vaccine development.”.
This research was conducted by scientists at the Centro Nacional de Investigaciones Cardiovasculares Carlos III and the Institute for Research in Biomedicine Barcelona.
This project was supported by the “la Caixa” Foundation (ID 100010434) INPhINIT Fellowship code LCF/BQ/IN17/11620074 (I.H.-M.). I.M. lab work was supported by Fundación Fero. P.H.-A. is supported by RYC2022-036516-I. Work in the D.S. laboratory received support from the CNIC; Ministerio de Ciencia, Innovación y Universidades (MICIU) PID2022-137712OB-I00, PDC2025-165319-I00, CPP2022-009762, and CPP2024-011365 MICIU/AEI/10.13039/501100011033 Agencia Estatal de Investigación, Unión Europea NextGenerationEU/PRTR; Comunidad de Madrid (P2022/BMD-7333 INMUNOVAR-CM); Scientific Foundation of the Spanish Association Against Cancer (AECC-PRYGN246642SANC); Worldwide Cancer Research WWCR-25-0080; European Union ERC-POC-2023-GA-101158245-ImnovAth; research agreement with Inmunotek S.L.; Fundación CRIS contra el cáncer (excellence2025_03); and “la Caixa” Foundation (LCF/PR/HR23/52430012 and LCF/PR/HR22/52420019). The S.K.W. laboratory and this work are supported by the IRB Barcelona, the European Union, and European Research Council’s Horizon Europe programme (ERC-2023-StG “MyTissue” project number 101117470) and by grants RYC2022-036400-I and PID2022-140715OA-I00 from MCIN/AEI/10.13039/501100011033 Agencia Estatal de Investigación, Unión Europea NextGenerationEU/PRTR. IRB Barcelona receives institutional funding from the Spanish Ministry of Science and Innovation, through the Centres of Excellence Severo Ochoa Award, and from the CERCA Programme/Generalitat de Catalunya. M.A.Z. and J.J.F. were supported by “la Caixa” Foundation under the project code LCF/PR/HR22/52420011 and by Fundació “La Marató TV3” (grant 202314-31). J.A.E. is supported by PID2024-158440OB-100, TED2024-158440OB-I00, and PID2021-127988OB-100, funded by MICIU/AEI/10.13039/501100011033 and the European Union “NextGenerationEU”/Plan de Recuperación Transformación y Resiliencia/PRTR; CIBERFES (CB16/10/00282); Fundación “la Caixa” (LCF/PR/HR23/52430010); and ERC-2024-ADG (GA 101198761). N.S.C. was funded by 5R01CA290678. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MICIU, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (CEX2020-001041-S funded by MICIU/AEI/10.13039/501100011033).
