洛桑大学何秉智研究组取得一项新突破。他们的论文发现了蛋白酶体引导的血红素信号轴有助于T细胞衰竭。相关论文于2026年3月18日发表在《自然》杂志上。

在这里，该课题组人员发现由于去极化线粒体的积累，耗尽的CD8⁺ T细胞增加了蛋白酶体的活性，这驱动了线粒体蛋白的选择性降解和通过血液蛋白分解释放调节性血红素。反过来，增加的调节性血红素破坏BACH2介导的转录调节，从而加剧T细胞衰竭和损害干细胞样特性。抑制调节性血红素的核输入可阻止BACH2降解，增强抗原特异性T细胞的抗肿瘤作用。

研究小组发现人CD19⁺嵌合抗原受体(CAR)-T细胞对B细胞急性淋巴细胞白血病患者的治疗效果与其CAR-T细胞中的蛋白酶体基因标记负相关。在硼替佐米存在下制造CAR-T细胞，硼替佐米是一种经FDA批准的蛋白酶体抑制剂，可防止T细胞衰竭并提高治疗效果。他们的发现确定了一个由线粒体完整性控制的蛋白酶体引导的血红素信号轴，作为CD8⁺ T细胞衰竭的调节剂，并提出了利用这一途径优化过继细胞免疫治疗的创新治疗策略。

研究人员表示，去极化线粒体的积累导致T细胞衰竭，但确切的机制尚不清楚。

附：英文原文

Title: Proteasome-guided haem signalling axis contributes to T cell exhaustion

Author: Xu, Yingxi, Shangguan, Yangtao, Chuang, Yu-Ming, Chang, Tzu-Hsuan, Liu, Wenbing, Peng, Jhan-Jie, Garnica, Josep, Xie, Leling, Hsueh, Pei-Chun, Lin, Mei-Chun, Wang, Yi-Hao, Hajdu, Karina Lobo, Wu, Yibo, Akrami, Maryam, Wang, Chen, Kohl, Anna, Zippelius, Alfred, Qi, Wei, Wang, Min, Budiarto, Bugi Ratno, Chen, Shih-Yu, Xiao, Zhengtao, Vardaka, Panagiota, Roychoudhuri, Rahul, Bai, Zhiliang, Fan, Rong, Carmona, Santiago, Yu, Yi-Ru, Scheiermann, Christoph, Wang, Jianxiang, Ho, Ping-Chih

Issue&Volume: 2026-03-18

Abstract: The accumulation of depolarized mitochondria commits T cells to exhaustion1,2,3, yet the precise mechanism remains unclear. Here we find that exhausted CD8+ T cells increase proteasome activity owing to the accumulation of depolarized mitochondria, which drives the selective degradation of mitochondrial proteins and the release of regulatory haem through haemoprotein breakdown. In turn, increased regulatory haem disrupts BACH2-mediated transcriptional regulation, thereby exacerbating T cell exhaustion and compromising stemness-like properties. Inhibition of nuclear import of regulatory haem prevents BACH2 degradation and enhances the anti-tumour efficacy of antigen-specific T cells. We find that the therapeutic efficacy of human CD19+ chimeric antigen receptor (CAR)-T cells in patients with B cell acute lymphoblastic leukaemia negatively correlates with the proteasome gene signature in their CAR-T cells. Manufacturing CAR-T cells in the presence of bortezomib, an FDA-approved proteasome inhibitor, prevents T cell exhaustion and improves therapeutic efficacy. Our findings identify a proteasome-guided haem signalling axis, governed by mitochondrial integrity, as a regulator of CD8+ T cell exhaustion and propose innovative therapeutic strategies that exploit this pathway to optimize adoptive cellular immunotherapy.

DOI: 10.1038/s41586-026-10250-y

Source: https://www.nature.com/articles/s41586-026-10250-y