美国俄亥俄州立大学Stanley Ching-Cheng Huang课题组的研究认为癌症抑制巨噬细胞中的线粒体伴侣活性以驱动免疫逃避。相关论文发表在2025年10月29日出版的《自然—免疫学》杂志上。

在这里，研究小组确定TNF受体相关蛋白-1 (TRAP1)，一种线粒体HSP90伴侣，作为代谢检查点，抑制氧化呼吸和限制巨噬细胞抑制功能。在TME中，TRAP1通过TIM4-AMPK信号下调，其缺失增强了免疫抑制活性，限制了促炎能力，促进肿瘤免疫逃逸。机制上，TRAP1抑制增强了电子传递链活性，提高了α-酮戊二酸/琥珀酸比值，重塑了线粒体稳态。α-酮戊二酸的积累进一步增强了JMJD3介导的组蛋白去甲基化，建立了加强免疫抑制状态的转录程序。通过靶向TIM4和JMJD3来恢复TRAP1，重新编程TAMs，破坏免疫逃避性TME并增强抗肿瘤免疫。这些发现证实了TRAP1是一个整合代谢和表观遗传控制抑制TAM功能的关键调节因子，并将TRAP1途径定位为癌症免疫治疗的一个有希望的靶点。

据悉，与线粒体功能失调的肿瘤浸润性T细胞相反，肿瘤相关巨噬细胞（TAMs）在营养受限的肿瘤微环境（TME）中保持线粒体活性，以维持免疫抑制。

附：英文原文

Title: Cancer suppresses mitochondrial chaperone activity in macrophages to drive immune evasion

Author: Zhao, Haoxin, Park, Jaeoh, Wang, Yuzhu, Chou, Yi-Ju, Li, Lemin, Raines, Lydia N., Hsu, Michael, Lin, Ching-Cheng, Cao, Wei, Ouyang, Yuli, Chen, Heng-Yi, Zheng, Linghua, Li, Zihai, Huang, Alex Y., Ho, Ping-Chih, Lio, Chan-Wang Jerry, Huang, Stanley Ching-Cheng

Issue&Volume: 2025-10-29

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.

DOI: 10.1038/s41590-025-02324-2

Source: https://www.nature.com/articles/s41590-025-02324-2