工程化益生菌用于肿瘤靶向联合化学免疫治疗
Engineered probiotics for tumor-targeted combination chemoimmunotherapy.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
葡萄糖剥夺的肿瘤微环境激活 AMP 活化蛋白激酶驱动过继转移的 T 辅助 9 细胞衰老
英文原题：Glucose-deprived tumor microenvironment activates AMP-activated protein kinase to drive adoptively transferred T helper 9 cell senescence.
查看英文原题
Glucose-deprived tumor microenvironment activates AMP-activated protein kinase to drive adoptively transferred T helper 9 cell senescence.
分数与星级只用于站内排序 —— 不代表疗效、安全性或个人适用性。
研究概要
辅助性T细胞9（Th9）细胞在针对实体瘤的过继细胞治疗（ACT）中显示出前景。
中文摘要
辅助性T细胞9（Th9）细胞在针对实体瘤的过继细胞治疗（ACT）中显示出前景。然而，其临床应用面临在肿瘤微环境（TME）中持久性方面的挑战。
我们观察到，肿瘤生长逐渐降低TME中的葡萄糖浓度，伴随转移的Th9细胞及其效应功能下降，这是由于Th9细胞衰老所致。恢复葡萄糖浓度可抑制Th9细胞衰老，从而改善其持久性。在机制上，葡萄糖剥夺激活AMP活化蛋白激酶（AMPK），触发下游亮氨酸拉链和无菌α基序激酶（ZAK）-核因子κB（NF-κB）诱导激酶（NIK）级联反应，抑制非经典NF-κB信号传导和白细胞介素（IL）-9产生，最终驱动Th9细胞衰老。ZAK相关的嵌合抗原受体（CAR）-T细胞衰老与人类癌症中治疗效果受损相关。靶向ZAK可使Th9细胞恢复活力，并增强CAR-Th9细胞对实体瘤的疗效。
我们的研究揭示了一种营养剥夺促进Th9细胞衰老从而损害持久性的机制，突出了靶向ZAK以使CAR-Th9细胞恢复活力用于实体瘤治疗的潜力。
展开英文摘要原文
T helper 9 (Th9) cells show promise for adoptive cell therapy (ACT) against solid tumors.
However, clinical application faces challenges regarding their persistence in the tumor microenvironment (TME).
We observed that tumor growth gradually reduced glucose concentrations in the TME, accompanied by a decline in transferred Th9 cells and their effector functions, due to Th9 cell senescence. Restoring glucose concentrations suppressed Th9 cell senescence, thereby improving their persistence.
Mechanistically, glucose-deprivation-activated AMP-activated protein kinase (AMPK), triggering downstream leucine-zipper and sterile-α motif kinase (ZAK)-nuclear factor κB (NF-κB)-inducing kinase (NIK) cascades that suppressed noncanonical NF-κB signaling and interleukin (IL)-9 production, ultimately driving Th9 cell senescence. ZAK-associated chimeric antigen receptor (CAR)-T cell senescence was linked to compromised therapeutic efficacy in human cancers. Targeting ZAK rejuvenated Th9 cells and enhanced CAR-Th9 cell efficacy against solid tumors.
Our study uncovers a mechanism by which nutrient deprivation promotes Th9 cell senescence to compromise persistence, highlights the potential of targeting ZAK to rejuvenate CAR-Th9 cells for solid tumor therapy.
论文信息
- 作者
- Fu J、Pei S、Du J、Deng X、Wang X、Li T、Huang H、Ye J
- 第一作者单位
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.China
- 通讯作者单位
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: ycxiao@sibs.ac.cn.China
- 期刊
- Immunity2026 Oct 1
- 原文标识
- PubMed 42822442 · DOI 10.1016/j.immuni.2026.09.004