Mortezaee Keywan
Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
Cancer and Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.
Hum Cell. 2025 Aug 25;38(5):150. doi: 10.1007/s13577-025-01280-1.
Regulatory T cell (Treg) immunome profile and targets in antiprogrammed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) is a subject of extensive research, but there are still complexities in the area due to the nature of tumor microenvironment (TME). TME of solid tumors contains factors exerting a range of effects on Tregs including development, recruitment, expansion, stability and their immunosuppressive activity. Anti-PD-1 secondarily causes replenishment of intratumoral Tregs, which further intensify tumor immunosuppression. Besides, Treg depletion may also compromise immune checkpoint inhibitor (ICI) efficacy in addition to its other adversarial effects. Thus, a desired ICI booster is to use agents preferentially acting on intratumoral Tregs. Modulation of hypoxia, and regulation of Treg-related cytokines, chemokines, receptors and chromatin modifying factors in tumor TME provide supplementary approaches to anti-PD-(L)1. Factors acting on Tregs have diverse or even dual functions in TME. Treg expansion inhibitory and immunosuppressive tumor-associated macrophage (TAM) recruitment stimulatory effects of stimulator of interferon genes (STING), effector suppressor Treg activating and tumor-specific CD8 T cell stimulatory effects of interleukin type 2 receptor alpha (IL-2Rα, also called CD25), cell type-dependent dual activities of CXCR3 and inducible T cell costimulatory (ICOS), exposure time-dependent dual effects of glucocorticoid-induced TNFR-related protein (GITR) and CD70 on Tregs and T cells, and exposure level-dependent dual activities of IFN-γ on Tregs are examples require consideration in designing Treg-based strategies. The main direction of this review is to provide updated information about targeting modulators of intratumoral Tregs with agents/compounds aiming to expand anti-PD-(L)1 efficacy and durability in solid tumors.
调节性T细胞（Treg）免疫组特征及抗程序性细胞死亡蛋白1（PD-1）/程序性细胞死亡配体1（PD-L1）中的靶点是广泛研究的课题，但由于肿瘤微环境（TME）的特性，该领域仍存在复杂性。实体瘤的TME包含对Tregs产生一系列影响的因素，包括发育、募集、扩增、稳定性及其免疫抑制活性。抗PD-1继而导致肿瘤内Tregs的补充，这进一步加剧了肿瘤免疫抑制。此外，Treg耗竭除了具有其他不利影响外，还可能损害免疫检查点抑制剂（ICI）的疗效。因此，理想的ICI增强剂是使用优先作用于肿瘤内Tregs的药物。调节缺氧以及调节肿瘤TME中与Treg相关的细胞因子、趋化因子、受体和染色质修饰因子为抗PD-（L）1提供了补充方法。作用于Tregs的因素在TME中具有多样甚至双重功能。干扰素基因刺激剂（STING）对Treg扩增的抑制作用和对免疫抑制性肿瘤相关巨噬细胞（TAM）募集的刺激作用、白细胞介素2受体α（IL-2Rα，也称为CD25）对效应性抑制性Treg的激活作用和对肿瘤特异性CD8 T细胞的刺激作用、CXCR3和诱导性T细胞共刺激分子（ICOS）的细胞类型依赖性双重活性、糖皮质激素诱导的肿瘤坏死因子相关蛋白（GITR）和CD70对Tregs和T细胞的暴露时间依赖性双重作用，以及干扰素-γ对Tregs的暴露水平依赖性双重活性，这些都是在设计基于Treg的策略时需要考虑的例子。本综述的主要方向是提供有关使用药物/化合物靶向肿瘤内Tregs调节剂的最新信息，旨在扩大抗PD-（L）1在实体瘤中的疗效和持久性。
