Regulatory T Cells as a Double-Edged Sword in Cancer Immunotherapy : Annals of Oncology | May 2026
Introduction
Regulatory T cells (Tregs) are central mediators of immune tolerance and immune homeostasis. In cancer, however, these same suppressive functions are frequently exploited by tumors to evade antitumor immunity, making Tregs an increasingly important therapeutic target in modern immuno-oncology.
Problem Statement
Although depletion or functional inhibition of Tregs can enhance antitumor immune responses, indiscriminate disruption of Treg biology risks severe immune-related toxicities and systemic autoimmunity. The challenge is therefore to selectively target intratumoral Tregs while preserving peripheral immune tolerance.
Summary
This comprehensive review examines the evolving role of Treg-directed therapies in cancer immunotherapy and highlights both the therapeutic promise and biologic complexity of this strategy. Intratumoral Tregs suppress cytotoxic antitumor responses through multiple mechanisms, including IL-10 and TGF-β secretion, IL-2 consumption, metabolic competition, and inhibitory receptor signaling via CTLA-4, TIGIT and related checkpoints. High Treg infiltration is generally associated with poor clinical outcomes across many solid tumors, although prognostic implications vary by tumor type and immune contexture. Advances in single-cell and spatial profiling have demonstrated that tumor-associated Tregs possess distinct transcriptional, metabolic and spatial programs compared with peripheral Tregs, including enrichment of FOXP3+Helios+CCR8+ phenotypes that may serve as biomarkers and therapeutic targets. Current therapeutic approaches fall into three principal categories: direct depletion strategies using antibodies against CD25, CCR4 or CCR8; functional inhibition through checkpoint blockade targeting CTLA-4 or TIGIT; and disruption of metabolic pathways supporting Treg fitness, including PI3K and adenosine signaling. Novel IL-2 variants designed to preferentially modulate effector immune cells while limiting Treg expansion are also under active investigation. Despite encouraging preclinical activity, clinical translation has been complicated by narrow therapeutic windows and high-grade immune toxicities resulting from systemic immune dysregulation. Emerging strategies therefore focus on selectively impairing intratumoral Tregs while sparing systemic immune control, often through combinatorial approaches with PD-1 or PD-L1 blockade. The review emphasizes that deeper understanding of Treg heterogeneity, tissue-specific biology and metabolic dependencies will be essential for developing safer and more effective next-generation cancer immunotherapies.
