The surprising dual role: how Tregs, which normally suppress the immune system, can sometimes help fight tumors

Every year, millions of cancer patients worldwide face treatment challenges due to resistance to immunotherapy. Traditional theory suggests that Tregs promote tumor progression by suppressing immune responses. However, a comprehensive review published in the Journal of Translational Medicine, integrating cutting-edge technologies such as single-cell sequencing, reveals that specific subpopulations of Tregs or, under specific conditions, can reversibly act as “anti-tumor sentinels.” 

“Tregs play a double-edged role in inflammation-related malignant tumors such as colorectal cancer,” explained Professor Peng Luo, the corresponding author of the study. “They can alleviate harmful inflammation while specific subpopulations can secrete IFN-γ to activate anti-tumor immune responses. Crucially, their function dynamically evolves with tumor progression exerting anti-tumor effects in early stages but potentially shifting to pro-tumor effects in advanced disease.”

The study mechanistically delineates three principal pathways. First, fragile Tregs secrete IFN-γ under hypoxic conditions, directly inducing tumor cell cytotoxicity. second, Th1-like Tregs (T-bet+FoxP3+) enhance cytotoxic T lymphocyte function through IL-10-dependent STAT3 phosphorylation, boosting granzyme B production. Third, Stable Tregs inhibit mast cell degranulation via OX40-OX40L ligation and polarize tumor-associated macrophages away from pro-metastatic M2 phenotypes.

"This represents the identification of a master regulatory switch within the immune system," emphasized co-corresponding author Professor Ting Wei. “Selectively depleting tumour-infiltrating Tregs or inducing their conversion to anti-tumour subtypes can further enhance tumour killing and reduce systemic adverse reactions associated with traditional immunotherapy.