Figure 1.

Multiple immunosuppressive mechanisms of Tregs. Treg cells express high-affinity IL-2 receptors, with CD25 as the α subunit of this receptor. In contrast, the IL-2 receptors on Tconv comprise only β and γ subunits and are of lower affinity. Tregs competitively bind IL-2 in the tumor microenvironment, causing a relative deficiency of IL-2 in Tconv and suppressing T cell effector functions. Tregs highly express CTLA-4 and bind to CD80/86 ligands on APCs. This not only inhibits APC function but also reduces the binding of CD80/86 expressed by APCs to CD28 molecules on T cells. As a result, the activation of Teff is attenuated. Additionally, suppression of DC cells by Tregs leads to overexpression of IDO, which decreases tryptophan and leads to kynurenine accumulation in the TME. This results in effector T cell exhaustion and dampens anti-tumor immunity. Tregs secrete immunosuppressive cytokines, such as IL-10, IL-35, and TGF-β, which inhibit the activity of T cells and APC cells. They also secrete perforin and granzyme B to directly lyse effector immune cells. Additionally, Tregs overexpress CD39 and CD73, converting ATP in the TME into adenosine, which inhibits the functions of various immune cells, such as DC and Tconv. Tregs also upregulate chemokines like CCL4, CCR5, CCR8, and CCR10, facilitating their accumulation in the tumor. In addition, Tregs overexpress several immune checkpoint molecules, including PD-1, LAG-3, TIM-3, TIGIT, and VISTA, which suppress anti-tumor effector cells. Treg also upregulate co-stimulatory molecules such as ICOS, GITR, and CD27, which enhance Treg activity and proliferation.