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
真菌来源的纤维二糖代谢通路为 T 细胞供能从而绕过瘤内葡萄糖竞争
英文原题：Fungal-derived cellobiose metabolic pathway fuels T cells to bypass intratumoral glucose competition.
查看英文原题
Fungal-derived cellobiose metabolic pathway fuels T cells to bypass intratumoral glucose competition.
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中文摘要
实体瘤具有免疫抑制微环境，通过对葡萄糖的贪婪消耗抑制TIL（肿瘤浸润淋巴细胞）（TILs）。我们试图通过为它们提供一种专属燃料来源来恢复 TIL 功能。葡萄糖二糖纤维二糖是纤维素的构建单元，含有 β-1,4-糖苷键，动物（或其肿瘤）无法水解该键，但真菌和微生物已进化出酶，可将纤维二糖分解代谢为可利用的葡萄糖。我们用两种来源于真菌的蛋白装备了小鼠 T 细胞和人嵌合抗原受体（CAR）-T 细胞，这些蛋白能够导入和水解纤维二糖，并且我们证明在葡萄糖撤除期间补充纤维二糖可恢复关键抗肿瘤 T 细胞功能：活力、增殖、细胞因子产生和细胞毒性杀伤。被提供纤维二糖的工程化 T 细胞抑制肿瘤生长并延长生存期。提供对一种天然二糖的专属获取可增强癌症免疫疗法。这种方法可用于回答跨多种细胞类型、生物学过程和疾病的葡萄糖代谢问题。
展开英文摘要原文
Solid tumors harbor immunosuppressive microenvironments that inhibit tumor-infiltrating lymphocytes (TILs) through the voracious consumption of glucose.
We sought to restore TIL function by providing them with an exclusive fuel source. The glucose disaccharide cellobiose, which is the building block of cellulose, contains a -1,4-glycosidic bond that animals (or their tumors) cannot hydrolyze, but fungi and microbes have evolved enzymes to catabolize cellobiose into useful glucose.
We equipped mouse T cells and human chimeric antigen receptor (CAR)-T cells with two proteins derived from fungi that enable import and hydrolysis of cellobiose, and we demonstrated that cellobiose supplementation during glucose withdrawal restores key anti-tumor T-cell functions: viability, proliferation, cytokine production, and cytotoxic killing.
Engineered T cells offered cellobiose suppress tumor growth and prolong survival. Offering exclusive access to a natural disaccharide augments cancer immunotherapies. This approach could be used to answer questions about glucose metabolism across many cell types, biological processes, and diseases.
论文信息
- 作者
- Miller ML、Thauland TJ、Nagarajan SS、Zuo WE、Moreno Lastre MA、Butte MJ
- 第一作者单位
- Molecular Biology Institute, UCLA, Los Angeles, CA, USA; Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, UCLA, Los Angeles, CA, USA.United States
- 通讯作者单位
- Molecular Biology Institute, UCLA, Los Angeles, CA, USA; Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, UCLA, Los Angeles, CA, USA; Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA, USA; Department of Human Genetics, UCLA, Los Angeles, CA, USA. Electronic address: mbutte@mednet.ucla.edu.United States
- 期刊
- Cell2026 Mar 19
- 原文标识
- PubMed 41742411 · DOI 10.1016/j.cell.2026.01.015