Nature子刊：华人学者发现癌症免疫治疗新靶点——TRAP1

Core Viewpoint - The study identifies TRAP1 as a mitochondrial chaperone that is suppressed by cancer, leading to immune evasion, and suggests that restoring TRAP1 can reprogram tumor-associated macrophages (TAM) to enhance anti-tumor immunity, positioning the TRAP1 pathway as a promising new target for cancer immunotherapy [2][9]. Group 1 - TRAP1 is a mitochondrial HSP90 molecular chaperone that acts as a metabolic checkpoint, inhibiting oxidative respiration and limiting the suppressive function of macrophages [5]. - In the tumor microenvironment, TRAP1 expression is downregulated through the TIM4-AMPK signaling pathway, and its absence enhances immune suppressive activity while promoting tumor immune evasion [6]. - Inhibition of TRAP1 increases electron transport chain activity and raises the ratio of α-ketoglutarate to succinate, reshaping mitochondrial homeostasis and leading to enhanced immune suppression through JMJD3-mediated histone demethylation [6]. Group 2 - Targeting TIM4 and JMJD3 to restore TRAP1 can reprogram TAM, disrupt the immune evasion of the tumor microenvironment, and enhance anti-tumor immunity [7]. - The findings establish TRAP1 as a key regulatory factor integrating metabolic and epigenetic control of suppressive TAM functions, highlighting the TRAP1 pathway as a promising new target for cancer immunotherapy [9].