Treg cells in autoimmunity and cancer immunotherapy

Regulatory T (Treg) cells, identified over two decades ago, are pivotal in maintaining immune tolerance and preventing autoimmunity. Extensive research has revealed their central roles in autoimmune diseases, inflammation, and cancer, leading to the development of targeted therapeutics. Treg cell differentiation and function are primarily regulated by three key molecules: the transcription factor FOXP3, and the immune regulators CTLA-4 and TGF-β1, whose absence results in severe autoimmunity. CD25, the IL-2 receptor α-chain, is a characteristic surface marker distinguishing Treg cells from other CD4⁺ T cells. Defective Treg cell development or function contributes to autoimmune disorders such as colitis, diabetes, multiple sclerosis, and arthritis. On the other hand, tumors promote Treg cell generation to cause immunosuppression within the tumor microenvironment. Notably, Treg cell pathways exhibit tissue-specific regulation, reflecting the functional diversity and adaptability of this essential immune subset. Several laboratories have contributed to the understanding of the various flavors of Treg cells.This issue focuses on articles exploring mechanisms that inform therapeutic strategies targeting regulatory T (Treg) cells in both autoimmune and malignant diseases. Enhancing Treg function represents a promising approach for treating autoimmune and inflammatory disorders, whereas depletion or inhibition of Treg cells can boost anti-tumor immunity in cancer. However, these opposing strategies present significant challenges. For instance, systemic depletion of Treg cells—such as with ipilimumab (Yervoy®, anti–CTLA-4 antibody)—can augment anti-tumor responses but often leads to severe immune-related adverse events, including colitis, hepatitis, and dermatitis. A critical question remains whether tumor-specific Treg cells can be selectively targeted without compromising systemic immune tolerance. Although bispecific agents like TGF-β/PD-L1 inhibitors showed promise in preclinical and early clinical studies, they failed to improve efficacy in phase 3 trials and produced greater toxicity. Current research efforts aim to refine Treg-targeted therapies by developing localized delivery systems, tumor-restricted antibodies, and combinatorial regimens that mitigate adverse events while preserving therapeutic benefit. Together, these articles highlight the ongoing efforts to achieve a delicate balance between immune activation and tolerance—an essential goal for safely and effectively harnessing Treg cell biology in human disease.Articles of interest include the following topics:• Treg cells in autoimmune disease and therapeutic targets• TGFβ1 and CTLA-4 pathways for cancer immunotherapy• Regulatory cytokines and checkpoint inhibitors for autoimmunity• Current clinical trials targeting Treg cells for cancer and autoimmunity• Signaling pathways for drug development for both cancer and autoimmunity Topic editors: Ramireddy Bommireddy, Ram Raj Singh Source: https://www.frontiersin.org/research-topics/76483/treg-cells-in-autoimmunity-and-cancer-immunotherapy