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Cancer suppresses mitochondrial chaperone activity in macrophages to drive immune evasion

Haoxin Zhao^1,2, Jaeoh Park^3,4, Yuzhu Wang^5,6

¹Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH, USA.

Nature Immunology

|October 30, 2025

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.

Insights

Tumor-associated macrophages (TAMs) use TRAP1 (TNF receptor-associated protein-1) to limit their suppressive function. Restoring TRAP1 reprograms TAMs, enhancing antitumor immunity and disrupting immune evasion in the tumor microenvironment.

Area of Science:

Immunology
Metabolic pathways
Cancer biology

Background:

Tumor-associated macrophages (TAMs) promote tumor immune evasion by maintaining mitochondrial activity in the nutrient-limited tumor microenvironment (TME).
Dysfunctional mitochondria in T cells contrast with the preserved mitochondrial function in TAMs, contributing to immunosuppression.

Purpose of the Study:

To identify metabolic checkpoints regulating TAM function within the TME.
To investigate the role of TNF receptor-associated protein-1 (TRAP1) in controlling macrophage metabolism and immunosuppressive activity.

Main Methods:

Investigated TRAP1's role as a mitochondrial chaperone and metabolic regulator in TAMs.
Analyzed the effects of TRAP1 downregulation via TIM4-AMPK signaling on macrophage function and mitochondrial homeostasis.
Examined the impact of TRAP1 suppression on electron transport chain activity, α-ketoglutarate/succinate ratios, and JMJD3-mediated epigenetic modifications.

Main Results:

TRAP1 acts as a metabolic checkpoint, restraining oxidative respiration and limiting TAM suppressive functions.
TRAP1 downregulation in the TME enhances macrophage immunoinhibitory activity, reduces proinflammatory capacity, and promotes tumor immune escape.
TRAP1 suppression augments mitochondrial electron transport chain activity, alters the α-ketoglutarate/succinate ratio, and promotes JMJD3-mediated histone demethylation, reinforcing immunosuppression.

Conclusions:

TRAP1 is a critical regulator integrating metabolic and epigenetic control of TAM function.
Restoring TRAP1 by targeting TIM4 and JMJD3 reprograms TAMs, disrupts the immune-evasive TME, and enhances antitumor immunity.
The TRAP1 pathway represents a promising therapeutic target for cancer immunotherapy.

Read full analysis

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