ArticleImmunity2025
Mitochondrial complex IV remodeling in tumor-associated macrophages amplifies interferon signaling and promotes anti-tumor immunity.
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Article in Immunity, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21citing papers in PubMed
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Who cites it
21 citing papers in PubMed.
- CD1d remodels the tumor-infiltrating myeloid populations controlling antitumor immunity.The Journal of experimental medicine · 2026Article
- Tissue-Resident Macrophage in Inflammation and Cancer.MedComm · 2026Review
- All-optical multimodal mapping of single-cell-type-specific metabolic activities via REDCAT.Nature methods · 2026Article
- Adaptation of OXPHOS biogenesis to cellular requirements.Protein science : a publication of the Protein Society · 2026Review
- Driving tumor-associated macrophages to a CXCL9Cell reports. Medicine · 2026Article
- Loss of NCCRP1 overcomes immune evasion in lung adenocarcinoma.Journal for immunotherapy of cancer · 2026Article
- Multi-omic analysis reveals nitric oxide dependent remodeling in classically activated macrophages and identifies negative regulation mediated by AKR1A1.Redox biology · 2026Article
- A community machine learning challenge to predict the effects of gene perturbations on T cell differentiation for cancer immunotherapy.bioRxiv : the preprint server for biology · 2026Article
- Novel Organelle-Based Intracellular Immunity with Mechanistic and Therapeutic Implications.Barrier immunity · 2026Article
- The double-edged sword role of tumor-associated macrophages: preventing or causing resistance to immunotherapy.Journal of experimental & clinical cancer research : CR · 2026Review
- SPP1+ Macrophages and the Orchestration of Spatially Organized Immunosuppression in Cancer.Biomedicines · 2026Review
- Holding cancer in line: the role of the electron transport chain in tumor-associated macrophages.Frontiers in immunology · 2026Review
- Mitochondrial microprotein MOCCI controls neuroinflammation by altering glial activation states.Frontiers in immunology · 2026Article
- The application of nanotechnology in regulating mitochondrial function in tumor microenvironment for cancer therapy.Theranostics · 2026Review
- Multi-omic analysis reveals nitric oxide dependent remodeling in classically activated macrophages and identifies negative regulation mediated by AKR1A1.bioRxiv : the preprint server for biology · 2026Article
- The Five-Decade Journey of Small Cell Lung Cancer.Cancer communications (London, England) · 2026Review
- Targeting the exosomal CaMK2A-ZDHHC3-GPX4 pathway reprograms tumor-associated macrophages and enhances anti-PD-1/PD-L1 immunotherapy in gastric cancer.International journal of biological sciences · 2026Article
- Targeting complex IV to alter the tumor microenvironment and boost macrophage antitumor immunity.Life metabolism · 2025Article
- Engineering a spatiotemporal macrophage circuit via STING phase separation to override immune suppression in pancreatic cancer.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
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Authors and funding
12 authors.
Megan L ClarkDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health (I3H), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Kamen P SimeonovTranslational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Center for Metastasis Research eXcellence (MET-X), Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Penn Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Walter K MowelDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health (I3H), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Michaël F MichielettoDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health (I3H), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Leonel JoannasDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health (I3H), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Jasmine M WrightDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health (I3H), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Isabel EricksonDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health (I3H), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Lexus R JohnsonInstitute for Immunology and Immune Health (I3H), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Rakesh KrishnanMachine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Departments of Bioengineering and Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Institute for Computational Science, University of Pennsylvania, Philadelphia, PA 19104, USA.
César de la Fuente-NúñezMachine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Departments of Bioengineering and Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Institute for Computational Science, University of Pennsylvania, Philadelphia, PA 19104, USA.
Andy J MinnInstitute for Immunology and Immune Health (I3H), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Jorge Henao-MejiaDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health (I3H), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Protective Immunity, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: jhena@pennmedicine.upenn.edu.
Funding
VIRAL VECTOR COREP30DK019525 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI MITCHELL A. LAZAR · 1986 to 2026
$48.3MHEMATOPOIESIS TRAINING GRANTT32DK007780 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI TONG, WEI · 1999 to 2023
$6.7MVMD-PhD Training in Infectious Disease-Related ResearchT32AI070077 · NIAID · UNIVERSITY OF PENNSYLVANIA · PI Michael Lee Atchison · 2008 to 2026
$3.5M3-Dimensional genomic architecture in innate lymphoid cells and allergic inflammationR01AI168240 · NIAID · UNIVERSITY OF PENNSYLVANIA · PI HENAO-MEJIA, JORGE, VAHEDI, GOLNAZ · 2022 to 2025
$3.2M3D genome organization of the Ets1-Fli1 locus controls allergic responsesR01AI168136 · NIAID · UNIVERSITY OF PENNSYLVANIA · PI Jorge Henao-Mejia, Golnaz Vahedi · 2023 to 2026
$3.1MNon-coding RNA regulation of Myeloid CellsR01CA294364 · NCI · UNIVERSITY OF PENNSYLVANIA · PI Jorge Henao-Mejia · 2024 to 2026
$2.6MRemodeling of the electron transport chain in macrophages by a novel peptide-miRNA axisF30AI154694 · NIAID · UNIVERSITY OF PENNSYLVANIA · PI CLARK, MEGAN LYNN · 2021 to 2022
$68kNCI NIH HHS R01 CA294364NIAID NIH HHS F30 AI154694NIAID NIH HHS R01 AI168136NIAID NIH HHS R01 AI168240NIAID NIH HHS T32 AI070077NIDDK NIH HHS P30 DK019525NIDDK NIH HHS T32 DK007780
Abstract
Tumor-associated macrophages (TAMs) influence tumor progression and immune checkpoint blockade (ICB) efficacy. Interferon (IFN)-TAMs predict better survival and ICB responses, yet the mechanisms governing IFN-TAMs remain unclear. Here, we identify NDUFA4, a complex IV subunit of the electron transport chain, as a functional switch controlling TAM function and anti-tumor immunity. NDUFA4 expression sustained pro-tumoral TAMs. However, intratumoral IFNs decreased NDUFA4 expression in TAMs via the cooperative action of NDUFA4L3 and miR-147, co-encoded by a conserved bifunctional transcript. Mechanistically, NDUFA4 repression increased mitochondrial DNA release into the cytoplasm and subsequent STING activation, thereby amplifying anti-tumor IFN-induced transcriptional programs in TAMs. Finally, we designed RNA-based therapeutics that leveraged the specificity of miR-147 for the Ndufa4 transcript to enhance ICB efficacy and inhibit B16 melanoma tumor growth. These findings uncover mitochondrial complex IV remodeling as a critical mechanism governing the functional adaptation of macrophages to distinct microenvironments with broad implications for immunotherapy.
Indexed as
InterferonsMelanoma, ExperimentalMitochondriaTumor-Associated MacrophagesAnimalsCell Line, TumorGene Expression Regulation, NeoplasticHumansMiceMice, Inbred C57BLMicroRNAsSignal TransductionTumor MicroenvironmentInterferonsMicroRNAscGAScomplex IVelectron transport chainimmune checkpoint blockadeinterferon-stimulated genesmitochondriaSTINGtumor-associated macrophagestumor immunitytumor microenvironment
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.