Tumor microenvironment-induced epigenetic reprogramming of Tregs and its impact on immunotherapy

The tumor microenvironment (TME) represents a complex system comprising various cells and extracellular matrix components that play a crucial role in tumor initiation and progression. While recent therapeutic strategies for predominantly focus on targeting tumor cells, their impact on other cellular components in the TME, such as regulatory T (Treg) cells, remains insufficiently understood. The cellular components of the TME include tumor cells, immune cells, tumor-associated stromal cells, and myeloid-derived suppressor cells. Notably, the role of Treg cells in tumor therapy has emerged as a significant research area of focus in recent years. Regulatory CD4⁺ T cells, characterized by the expression of the transcription factor Forkhead Box P3 (FOXP3) and the surface marker CD25, are pivotal in mediating immune suppression and maintaining immune tolerance and homeostasis. Current tumor treatments mainly rely on radiation and chemotherapy. Although innovative therapies such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapies have demonstrated promising outcomes, their efficacy is limited, benefiting only a small subset of patients. Epigenetic inhibitors are increasingly recognized as pivotal in cancer treatment; however, prior research has predominantly concentrated on their effects on the tumor itself, while overlooking the potential influence of these compounds on regulatory T cells (Tregs) within the tumor microenvironment (TME). The therapeutic viability of modulating Tregs within the TME remains uncertain. The intricate microenvironment of the TME significantly influences the distinct epigenetic landscape of tumor-infiltrating Treg cells, including modifications in DNA methylation, histone modifications, and chromatin remodeling. A comprehensive understanding of these epigenetic modifications and the underlying factors driving them could unveil novel strategies for cancer therapy. This approach would enhance the understanding of the critical role of Tregs in tumor therapy and facilitate the development of more effective targeted therapies by addressing the unique epigenetic characteristics of tumor-infiltrating Tregs.