Targeting genome organizer Satb1 in regulatory T cells safely and potently enhances cancer immunity

Introduction/Rationale: Rigorous research over the years has revealed that the cellular composition of the tumor microenvironment (TME) matters, and a major constituent that facilitates tumor progression is the regulatory T cell (Treg). Tregs are essential for maintaining immune homeostasis and preventing autoimmune conditions but can also be a detriment via their suppression of immune responses against cancer. The significance of Treg research is far-reaching as supported by the 2025 Nobel Prize in Physiology or Medicine awarded to Drs. Mary Brunkow, Fred Ramsdell and Shimon Sakaguchi, “for their discoveries concerning peripheral immune tolerance”. However, identifying differences in Treg subtypes to specifically disrupt the activities of tumor-promoting Tregs, without affecting Tregs that maintain immune homeostasis remain elusive. Here, we sought to discover how to blunt pro-tumorigenic Tregs without compromising the abilities of Tregs in mediating self-tolerance.

Methods: To this end, we used state-of-the-art methods in immunology, including high dimensional flow cytometry, lineage-specific loss-of-function studies and single-cell RNA sequencing, as well as multiple tumor models in animals to investigate these fundamental gaps in the field.

Results: In doing so, we discovered that expression of the genome organizer special AT-rich sequence binding protein 1 (Satb1) could readily separate two Treg subtypes: pro-tumorigenic Tregs (termed Satb1+) and immune-regulatory Tregs (termed Satb1-). Deletion of Satb1 specifically in Tregs impaired the function of Satb1+ pro-tumorigenic Tregs, leading to enhanced CD8+ T cell antitumor immune responses, and complete tumor eradication without any systemic autoimmune conditions. Notably, Satb1- Tregs remained intact in knockout mice and were necessary for maintaining immune homeostasis and preventing autoimmunity.

Conclusion: Our results reveal a key mechanism to safely and potently enhance cancer immunity without causing systemic autoimmune diseases.