Targeting Regulatory T Cells in Cancer Immunotherapy: Annals of Oncology | August 2026

Introduction:

Regulatory T cells (Tregs) are essential for maintaining immune tolerance and preventing autoimmune disease. However, within the tumour microenvironment, these same cells suppress antitumor immune responses, allowing cancers to evade immune surveillance. As immune checkpoint inhibitors become standard therapy across multiple malignancies, selectively targeting tumour-associated Tregs has emerged as an attractive strategy to enhance immunotherapy while overcoming treatment resistance.

Why was this review needed?

Intratumoral Tregs are a major mechanism of resistance to cancer immunotherapy.

High Treg infiltration is associated with poor outcomes in many solid tumors.

Current immune checkpoint inhibitors do not adequately overcome Treg-mediated immunosuppression.

Multiple novel agents targeting Tregs are entering clinical development.

The major challenge is enhancing antitumor immunity without triggering severe autoimmune toxicity.

Key Takeaways:

Tregs suppress antitumor immunity through multiple mechanisms, including inhibitory cytokines, CTLA-4 signaling, IL-2 consumption, and metabolic regulation of the tumor microenvironment.

Tumor-associated Tregs possess distinct transcriptional, metabolic, and spatial characteristics, creating opportunities for more selective therapeutic targeting.

Three major therapeutic strategies are under active investigation:

Treg depletion using antibodies against CD25, CCR4, and CCR8.

Functional inhibition through immune checkpoint targets such as CTLA-4 and TIGIT.

Metabolic modulation, including inhibition of adenosine signaling and the PI3K pathway.

Combination strategies pairing Treg-targeted therapies with PD-1/PD-L1 inhibitors may further enhance antitumor immune responses.

Emerging biomarkers such as FOXP3⁺Helios⁺CCR8⁺ Tregs may help identify patients most likely to benefit from selective Treg-targeted therapies.

A major limitation remains immune-related toxicity, as excessive depletion of Tregs can disrupt immune tolerance and lead to serious autoimmune complications.

Future therapies aim to selectively eliminate intratumoral Tregs while preserving peripheral immune regulation, maximizing efficacy while minimizing toxicity.

Clinical Impact:

Targeting regulatory T cells represents one of the most promising strategies for the next generation of cancer immunotherapy. Rather than replacing immune checkpoint inhibitors, Treg-directed therapies are expected to complement existing treatments by reversing immune suppression within the tumor microenvironment. Success will depend on developing highly selective approaches that preserve systemic immune tolerance while enhancing antitumor immunity. Biomarker-guided patient selection is likely to play a central role in future clinical implementation.

Bottom Line:

Regulatory T cells are critical mediators of tumor immune escape and represent an important emerging target for cancer immunotherapy. Novel strategies targeting CD25, CCR8, CTLA-4, TIGIT, IL-2 signaling, and Treg metabolism have the potential to enhance the efficacy of immune checkpoint inhibitors, provided immune-related toxicity can be minimized through selective targeting and biomarker-driven precision medicine.