Mitochondrial complex IV remodeling in tumor-associated macrophages amplifies interferon signaling and promotes anti-tumor immunity

  • Immunity. 2025 Jul 8;58(7):1670-1687.e12. doi: 10.1016/j.immuni.2025.06.006.
Megan L Clark  1 ,  Kamen P Simeonov  2 ,  Walter K Mowel  1 ,  Michaël F Michieletto  1 ,  Leonel Joannas  1 ,  Jasmine M Wright  1 ,  Isabel Erickson  1 ,  Lexus R Johnson  3 ,  Rakesh Krishnan  4 ,  César de la Fuente-Núñez  4 ,  Andy J Minn  3 ,  Jorge Henao-Mejia  5
Affiliations
  • 1. Department 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.
  • 2. Translational 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.
  • 3. Institute 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.
  • 4. Machine 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.
  • 5. Department 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: [email protected].
PMID: 40592341 DOI: 10.1016/j.immuni.2025.06.006
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.

Keywords
STING; cGAS; complex IV; electron transport chain; immune checkpoint blockade; interferon-stimulated genes; mitochondria; tumor immunity; tumor microenvironment; tumor-associated macrophages.
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