Fragility and Plasticity of CCR8+Tregs: Providing New Directions for Cancer Treatment

Abstract

Regulatory T cells (Tregs) are crucial for maintaining immune homeostasis. However, in the tumor microenvironment, tumor cells induce Tregs to exert immunosuppressive effects, leading to the failure of anti-tumor immunity. Traditional Treg clearance strategies, due to their lack of selectivity, damage peripheral normal Tregs during treatment, causing severe autoimmune side effects. This article analyzes the biological characteristics, fragility, and plasticity of CCR8⁺Tregs and their molecular mechanisms. The results show that CCR8⁺Tregs are specifically highly expressed on tumor-infiltrating Tregs, and after binding to the C-C Motif Chemokine Ligand 1 (CCL1), they maintain the stability of the Foxp3 transcriptional complex through the PI3K/AKT signaling axis. Blocking CCR8 signaling can trigger FOXO1 nuclear export and inhibit c-MAF expression, inducing IFN-γ-dependent fragility in Tregs. This fragility is the molecular basis of its functional plasticity, which can drive Tregs to reprogram to a Th1-like pro-inflammatory phenotype, thereby reshaping the TME from inhibition to activation. In summary, targeting the fragility and plasticity of CCR8⁺Tregs holds promise for achieving precise immune regulation, providing new insights for optimizing combined immunotherapy for tumors.