中国医学科学院李贵登等合作发现，揭示了甘露糖代谢重塑T细胞分化以增强抗肿瘤免疫。该项研究成果发表在2024年12月5日出版的《癌细胞》上。

细胞代谢状态深刻影响T细胞的分化、持久性和抗肿瘤疗效。研究人员对T细胞的单细胞代谢分析显示，甘露糖代谢减少是T细胞功能障碍的一个突出特征。相反，在体外和体内实验中，通过补充D-甘露糖来增强/恢复过继性转移T细胞的甘露糖代谢，可以增强抗肿瘤活性，并限制衰竭分化。

从机制上说，D-甘露糖处理诱导细胞内代谢编程，增加O-糖基-N-乙酰氨基葡萄糖转移酶（OGT）介导的β-catenin的O-糖基化，从而保持Tcf7的表达和表观遗传干性，从而促进T细胞中的干性样程序。

此外，补充D-甘露糖的体外扩增产生具有干细胞特性的过继治疗T细胞产物，即使经过广泛的长期扩增，也显示出增强的抗肿瘤功效。这些发现揭示了细胞内在甘露糖代谢作为CD8⁺ T细胞命运的生理调节剂，将增殖/扩增与分化解偶联，并强调了甘露糖调节在癌症免疫治疗中的治疗潜力。

附：英文原文

Title: Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity

Author: Yajing Qiu, Yapeng Su, Ermei Xie, Hongcheng Cheng, Jing Du, Yue Xu, Xiaoli Pan, Zhe Wang, Daniel G. Chen, Hong Zhu, Philip D. Greenberg, Guideng Li

Issue&Volume: 2024-12-05

Abstract: Cellular metabolic status profoundly influences T cell differentiation, persistence, and anti-tumor efficacy. Our single-cell metabolic analyses of T cells reveal that diminished mannose metabolism is a prominent feature of T cell dysfunction. Conversely, experimental augmentation/restoration of mannose metabolism in adoptively transferred T cells via D-mannose supplementation enhances anti-tumor activity and restricts exhaustion differentiation both in vitro and in vivo. Mechanistically, D-mannose treatment induces intracellular metabolic programming and increases the O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of β-catenin, which preserves Tcf7 expression and epigenetic stemness, thereby promoting stem-like programs in T cells. Furthermore, in vitro expansion with D-mannose supplementation yields T cell products for adoptive therapy with stemness characteristics, even after extensive long-term expansion, that exhibits enhanced anti-tumor efficacy. These findings reveal cell-intrinsic mannose metabolism as a physiological regulator of CD8+ T cell fate, decoupling proliferation/expansion from differentiation, and underscoring the therapeutic potential of mannose modulation in cancer immunotherapy.

DOI: 10.1016/j.ccell.2024.11.003

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00438-0