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Regulatory T cells in the tumour microenvironment

Nature Reviews Cancer volume 25, pages 703–722 (2025)Cite this article

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Abstract

The powerful suppressive capabilities of regulatory T (Treg) cells and their appreciable contribution to tumour progression make them attractive immunotherapeutic targets. However, their role in systemic immune homeostasis makes it important to find ways to specifically target tumour-infiltrating Treg cells while leaving the wider system unperturbed. It is also unknown whether therapies depleting or disrupting the function of tumour-infiltrating Treg cells will provide the greatest efficacy while limiting immune-related adverse events. In addition, Treg cells share much of their biology with conventional CD4+ T cells, introducing challenges when designing targeted immunotherapies. In this Review, we discuss recent advances in differentiating tumour-infiltrating Treg cells from their systemic and tissue-resident counterparts and understanding how the biology of tumour-infiltrating Treg cells differs from conventional CD4+ T cells. We also discuss how recent technological advances may enable the study of tumour-infiltrating Treg cells in even greater detail, helping to identify new targets for next-generation immunotherapeutic drugs.

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Fig. 1: Phenotypic and functional heterogeneity of tumour-infiltrating regulatory T cells.
Fig. 2: Mechanisms of major suppressive functions of regulatory T cells.
Fig. 3: Metabolic reprogramming and adaptation of tumour-infiltrating regulatory T cells.
Fig. 4: Therapeutic targeting of tumour-infiltrating regulatory T cells.

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Acknowledgements

We thank all members of the Vignali laboratory (Vignali-lab.com, @Vignali_Lab) for insights and constructive comments. The authors are supported by the US National Institutes of Health: P01 AI108545, R35 CA263850, P50 CA254865 and P50 CA097190 to D.A.A.V.; and R01 AI144422 to D.A.A.V. and C.J.W.

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  1. These authors contributed equally: Charlotte J. Imianowski, Qiang Chen.

Authors and Affiliations

  1. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Charlotte J. Imianowski, Qiang Chen, Creg J. Workman & Dario A. A. Vignali

  2. Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Charlotte J. Imianowski, Qiang Chen, Creg J. Workman & Dario A. A. Vignali

  3. Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Dario A. A. Vignali

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Contributions

C.J.I. and Q.C. researched data for the article, contributed substantially to discussion of the content and wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Dario A. A. Vignali.

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Competing interests

D.A.A.V. and C.J.W. have patents covering LAG3, with others pending, and are entitled to a share of net income generated from licensing of these patent rights for commercial development. D.A.A.V. is a cofounder and stockholder of Novasenta, Potenza, Tizona and Trishula; a stockholder of Werewolf; has patents licensed and royalties for BMS and Novasenta; a scientific advisory board member of Werewolf, Apeximmune and T7/Imreg Bio; a consultant for BMS, Regeneron, Ono Pharma, Peptone, Avidity Partners, Third Arc Bio, Peptone, Secarna and Curio Bio; and has been provided funding from BMS and Novasenta. C.J.I. and Q.C. declare no competing interests.

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Glossary

Anergy

An induced state of permanent unresponsiveness to antigen.

Antibody-dependent cellular cytotoxicity

(ADCC). The lysis of antibody-coated target cells by effector cells such as natural killer cells or macrophages, induced by the engagement of activating Fcγ receptors and subsequent release of cytotoxic granules.

Antibody-dependent cellular phagocytosis

(ADCP). The internalization and degradation of opsonized target cells, induced by the engagement of Fcγ receptors on effector cells such as myeloid cells and granulocytes.

Electron transport chain

A series of protein complexes found in the mitochondrial membrane that couple redox reactions to the generation of ATP by the formation of an electrochemical gradient.

Ferroptosis

A form of regulated cell death, dependent on iron, that involves the accumulation of lipid peroxides in cells.

Glycolysis

A metabolic pathway used to convert glucose to pyruvate or lactate and generate energy in the form of ATP.

Lactylation

A post-transcriptional modification involving the addition of a lactyl group to a lysine residue.

Oxidative phosphorylation

(OXPHOS). The process by which cells generate ATP through the transfer of electrons from NADH and FADH2 to oxygen.

Peripheral tolerance

A mechanism to control the self-reactivity of mature lymphocytes in the periphery, achieved by suppressing the production of self-reactive antibodies by B cells and inhibition of self-reactive effector T cells.

T follicular helper (TFH) cells

A subset of CD4+ helper T cells that develop under the direction of the master transcription factor BCL6 and are found in lymphoid tissue; they provide help for B cells to produce high-affinity antibodies.

Thymocytes

T cells that develop within the thymus.

Transendocytosis

The biological process in which cells bind to and capture cell-surface receptors from another cell for internalization and degradation.

Trogocytosis

The active process of plasma membrane acquisition by a recipient cell, including the transfer of membrane molecules.

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Imianowski, C.J., Chen, Q., Workman, C.J. et al. Regulatory T cells in the tumour microenvironment. Nat Rev Cancer 25, 703–722 (2025). https://doi.org/10.1038/s41568-025-00832-9

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