Engineering regulatory T cells (Tregs) has emerged as a powerful strategy to achieve durable, antigen-specific immune tolerance for autoimmune and inflammatory diseases. Advances in gene editing, synthetic biology, and cell manufacturing now enable the generation of CAR-Tregs, TCR-engineered Tregs, and metabolically or epigenetically enhanced Tregs with improved stability, specificity, and suppressive capacity. As these technologies move toward clinical translation, there is a critical need to integrate mechanistic knowledge, novel engineering approaches, and translational frameworks.

This Research Topic will gather cutting-edge studies and authoritative reviews on Treg engineering, including genetic modification, metabolic programming, stability determinants, preclinical disease models, and early clinical findings. The goal is to create a multidisciplinary forum for immunologists, cell engineers, and clinician-scientists to address challenges and opportunities in developing safe, scalable, and effective Treg-based therapies for autoimmune disorders. This collection will provide timely insights to accelerate innovation and translation in next-generation Treg therapies.

Autoimmune diseases remain a significant global health challenge, and current immunosuppressive therapies often provide incomplete control and carry long-term risks. Regulatory T cells (Tregs) play a central role in maintaining immune tolerance, and engineered Treg therapies—enabled by advances in gene editing, synthetic biology, and cell therapy manufacturing—represent a promising approach for achieving durable, targeted immune regulation.

This Research Topic seeks to consolidate emerging work that is shaping the engineered Treg therapy landscape. Areas of interest include genetic engineering platforms such as CAR-Tregs, TCR-modified Tregs, and CRISPR-edited Tregs; metabolic and epigenetic enhancements that improve Treg resilience in inflammatory environments; mechanistic insights into Treg identity, plasticity, and suppressive function; and preclinical or early clinical evidence demonstrating therapeutic potential.

We also encourage submissions addressing translational and manufacturing challenges, including GMP-compliant production, scalability, safety profiling, and regulatory considerations. By bringing together contributions from immunologists, cell engineers, and clinician-scientists, this collection will provide a comprehensive view of current advances and future directions in engineered Treg therapies, offering timely perspectives to accelerate the translation of next-generation Treg-based interventions for autoimmune disorders.

This Research Topic highlights innovations in regulatory T cell (Treg) therapies. Engineering and synthetic biology approaches—including CAR-Tregs, BAR-Tregs, antigen-specific TCR-Tregs, and CRISPR/Cas-based modifications—enhance Treg stability, function, and controlled activation, while optimizing trafficking and cytokine responses.

Mechanistic studies using transcriptional, epigenetic, and single-cell multi-omics analyses probe Treg identity, plasticity, and function. Metabolic programming addresses survival and suppressive capacity in inflammatory environments. Preclinical research in autoimmune and humanized models evaluates efficacy, persistence, safety, biomarkers, and potency. Manufacturing and regulatory efforts ensure GMP-compliant workflows, scalability, product consistency, genomic stability, and regulatory readiness.

By integrating these approaches, the field aims to develop safe, durable, and precisely targeted Treg-based immunotherapies for diverse autoimmune and inflammatory diseases.

Please note that manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this Research Topic.

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Programming tolerance: Treg engineering for next-generation immunotherapy for autoimmunity