Cancer suppresses mitochondrial chaperone activity in macrophages to drive immune evasion

  • Nat Immunol. 2025 Oct 29. doi: 10.1038/s41590-025-02324-2.
Haoxin Zhao  1  2 ,  Jaeoh Park  3  4 ,  Yuzhu Wang  5  6 ,  Yi-Ju Chou  1  2 ,  Lemin Li  1  2 ,  Lydia N Raines  5 ,  Michael Hsu  1 ,  Ching-Cheng Lin  2 ,  Wei Cao  5 ,  Yuli Ouyang  2 ,  Heng-Yi Chen  1 ,  Linghua Zheng  2 ,  Zihai Li  2 ,  Alex Y Huang  5  7  8 ,  Ping-Chih Ho  3  4 ,  Chan-Wang Jerry Lio  1 ,  Stanley Ching-Cheng Huang  9  10  11
Affiliations
  • 1. Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH, USA.
  • 2. Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
  • 3. Department of Oncology, University of Lausanne, Epalinges, Switzerland.
  • 4. Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.
  • 5. Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
  • 6. Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
  • 7. Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
  • 8. Center for Pediatric Immunotherapy, Angie Fowler AYA Cancer Institute, UH Rainbow Babies & Children's Hospital, Cleveland, OH, USA.
  • 9. Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH, USA. [email protected].
  • 10. Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. [email protected].
  • 11. Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. [email protected].
PMID: 41162642 DOI: 10.1038/s41590-025-02324-2
Abstract

Contrary to tumor-infiltrating T cells with dysfunctional mitochondria, tumor-associated macrophages (TAMs) preserve their mitochondrial activity in the nutrient-limited tumor microenvironment (TME) to sustain immunosuppression. Here we identify TNF receptor-associated protein-1 (TRAP1), a mitochondrial HSP90 chaperone, as a metabolic checkpoint that restrains oxidative respiration and limits macrophage suppressive function. In the TME, TRAP1 is downregulated through TIM4-AMPK signaling, and its loss enhances immunoinhibitory activity, limits proinflammatory capacity and promotes tumor immune escape. Mechanistically, TRAP1 suppression augments electron transport chain activity and elevates the α-ketoglutarate/succinate ratio, remodeling mitochondrial homeostasis. The resulting accumulation of α-ketoglutarate further potentiates JMJD3-mediated histone demethylation, establishing transcriptional programs that reinforce an immunosuppressive state. Restoring TRAP1 by targeting TIM4 and JMJD3 reprograms TAMs, disrupts the immune-evasive TME and bolsters antitumor immunity. These findings establish TRAP1 as a critical regulator integrating metabolic and epigenetic control of suppressive TAM function and position the TRAP1 pathway as a promising target for Cancer Immunotherapy.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-138280
    DTHIB
    99.82%, HSF1 Inhibitor
    target: HSP
    Research Areas: Cancer