2. Academic Validation
  3. Cancer suppresses mitochondrial chaperone activity in macrophages to drive immune evasion

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

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. stan.huang@osumc.edu.
  • 10 Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. stan.huang@osumc.edu.
  • 11 Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. stan.huang@osumc.edu.
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.

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