荷兰莱顿大学Ramon Arens课题组近日取得一项新成果。经过不懈努力，他们的研究发现细胞周期阻滞通过增强葡萄糖代谢和IL-2信号传导增强CD8⁺ T细胞效应功能。该研究于2026年1月19日发表于国际一流学术期刊《自然—免疫学》杂志上。

该研究组发现被激活的CD8⁺ T细胞在其细胞周期中仍然可以进行效应分化。细胞周期阻滞的CD8⁺ T细胞通过代谢重新编程进入高能量状态，在释放后能够快速增强增殖。这种代谢印记是由增加的营养摄取、储存和加工驱动的，导致细胞周期阻滞细胞的糖酵解增强。然而，对营养敏感的mTORC1通路并不重要。相反，在逮捕期间升高的白细胞介素-2产生激活STAT5信号，这支持被激活的CD8⁺ T细胞在逮捕后的扩张。通过免疫检查点阻断、过继性细胞转移和治疗性疫苗接种，在体内实现了CD8⁺ T细胞介导的肿瘤控制。因此，细胞周期进程中CD8⁺ T细胞分化的短暂解偶联计划了一个有利的代谢状态，支持效应T细胞介导的免疫疗法的疗效。

据介绍，细胞周期抑制化疗在癌症治疗中是一个广泛的主题。虽然主要目的是阻断肿瘤细胞增殖，但其临床疗效也涉及到同步增殖和分化的特异性效应CD8⁺ T细胞。当这些过程解偶联时，CD8⁺ T细胞是如何被编程的，就像在细胞周期抑制中发生的那样，目前还不清楚。

附：英文原文

Title: Cell cycle arrest enhances CD8+ T cell effector function by potentiating glucose metabolism and IL-2 signaling

Author: van Haften, Floortje J., van der Sluis, Tetje C., Hepp, Hanna S., Mlling, Nils, Nadafi, Reza, Sampadi, Bharath, van Duikeren, Suzanne, Mostert, J. Shirin, van der Sterre, Rosemarijn, van Veelen, Peter A., Heieis, Graham A., Veerkamp, Dominique M. B., Wesselink, Thomas H., Vleeshouwers, Ward, Beijnes, Macha, Pardieck, Iris N., van Horssen, Eralin L. F., de Groot, Anne F., van der Ploeg, Manon, Kroep, Judith R., de Miranda, Noel F. C. C., van der Zanden, Sabina Y., Neefjes, Jacques, Mei, Hailiang, Vertegaal, Alfred C. O., Everts, Bart, van der Burg, Sjoerd H., Arens, Ramon

Issue&Volume: 2026-01-19

Abstract: Cell cycle-inhibiting chemotherapeutics are widely used in cancer treatment. Although the primary aim is to block tumor cell proliferation, their clinical efficacy also involves specific effector CD8+ T cells that undergo synchronized proliferation and differentiation. How CD8+ T cells are programmed when these processes are uncoupled, as occurs during cell cycle inhibition, is unclear. Here, we show that activated CD8+ T cells arrested in their cell cycle can still undergo effector differentiation. Cell cycle-arrested CD8+ T cells become metabolically reprogrammed into a highly energized state, enabling rapid and enhanced proliferation upon release from arrest. This metabolic imprinting is driven by increased nutrient uptake, storage and processing, leading to enhanced glycolysis in cell cycle-arrested cells. The nutrient sensible mTORC1 pathway, however, was not crucial. Instead, elevated interleukin-2 production during arrest activates STAT5 signaling, which supports expansion of the energized CD8+ T cells following arrest. Transient arrest in vivo enables superior CD8+ T cell-mediated tumor control across models of immune checkpoint blockade, adoptive cell transfer and therapeutic vaccination. Thus, transient uncoupling of CD8+ T cell differentiation from cell cycle progression programs a favorable metabolic state that supports the efficacy of effector T cell-mediated immunotherapies.

DOI: 10.1038/s41590-025-02407-0

Source: https://www.nature.com/articles/s41590-025-02407-0