Targeting regulatory T cells for cancer immunotherapy: promises and pitfalls

Background: Regulatory T cells (Tregs) form a distinct subset of CD4⁺ T cells essential for maintaining immune balance and preventing autoimmunity by expressing CD25 and CTLA-4. Tregs, which are defined by the expression of the transcription factor FOXP3 in mice, restrain excessive immune activation through mechanisms such as interleukin 10 (IL-10) expression, transforming growth factor-β expression, metabolic regulation, acting as an IL-2 cytokine sink, and cell-to-cell interaction through co-inhibitory receptors. Although they are indispensable for immune tolerance, Tregs can be co-opted by tumors, where their suppressive activity promotes immune escape. High Treg infiltration within the tumor microenvironment has been linked to variable prognosis depending on the tumor type, highlighting Tregs’ contradictory roles as both guardians of tolerance and enablers of tumor progression. Design: In this review, we summarized Treg biology, Tregs’ contribution to cancer immunity, and emerging therapeutic strategies designed to modulate or deplete Tregs. We conducted a targeted literature review using PubMed/MEDLINE, Web of Science, ClinicalTrials.gov, and American Society of Clinical Oncology/European Society of Medical Oncology meeting libraries, complemented by manual reference screening. We also discussed the limitations of existing therapeutic approaches and outlined future directions. Results: Efforts to therapeutically modulate Tregs have focused on three main strategies: depletion (e.g. anti-CD25, anti-CCR4, or anti-CCR8 antibodies), functional blockade (e.g. targeting CTLA-4 or TIGIT), and disruption of metabolic pathways (e.g. adenosine or PI3K signaling) that support Tregs’ biological functions. Although preclinical studies have shown that targeting Tregs has antitumor effects, clinical trials have demonstrated variable efficacy and toxicity, reflecting the fine balance between immune activation and tolerance. Newer approaches aim to selectively impair intratumoral Tregs while preserving peripheral immune control, guided by T-cell subsets such as FOXP3⁺Helios⁺CCR8⁺ cells, which may help predict therapeutic response. Conclusion: A deeper understanding of Treg regulation is needed to unlock their therapeutic potential without compromising immune equilibrium.